Methods and uses related to administration of voclosporin

Abstract

Provided herein are methods of treatment and uses involving administration of voclosporin to a subject that has previously received a calcineurin inhibitor (CNI) such as cyclosporin, tacrolimus, or a derivative thereof for immunosuppression. In some aspects, the methods and uses relates to selecting a subject that has previously received a CNI such as cyclosporin, tacrolimus, or a derivative thereof for immunosuppression, for administration of voclosporin. In some aspects, the methods relate to treating or reducing adverse effects that can relate to immunosuppression using a CNI such as cyclosporin, tacrolimus, or a derivative thereof. In some aspects, the methods and uses involve administering a therapeutically effective amount of voclosporin to the selected subject.

Description

METHODS AND USES RELATED TO ADMINISTRATION OF VOCLOSPORINCross-Reference to Related Applications

[0001] This application claims priority from U.S. provisional application No. 63 / 457,084, filed April 4, 2023; 63 / 500,236, filed May 4, 2023; 63 / 501,361, filed May 10, 2023; 63 / 513,708, filed July 14, 2023, all entitled “METHODS AND USES RELATED TO ADMINISTRATION OF VOCLOSPORIN,” the contents of which are incorporated by reference in its entirety.Field

[0002] The present disclosure relates to methods of treatment and uses involving administration of voclosporin to a subject who has previously received a calcineurin inhibitor (CNI) such as cyclosporin, tacrolimus, or a derivative thereof for immunosuppression. In some aspects, the methods and uses relate to selecting a subject that has previously received a CNI such as cyclosporin, tacrolimus, or a derivative thereof for immunosuppression, for administration of voclosporin. In some aspects, the methods relate to treating or reducing adverse effects that can relate to immunosuppression using a CNI such as cyclosporin, tacrolimus, or a derivative thereof. In some aspects, the methods and uses involve administering a therapeutically safe and effective amount of voclosporin to the selected subject.Background

[0003] Traditional CNIs, such as cyclosporine and tacrolimus, both potent immunosuppressants, have been tested for use in the treatment of a variety of conditions, including use in conjunction with tissue transplant. Both of these compounds show long term nephrotoxicity. There is a need for a CNI that is an effective immunosuppressant but also tolerated for long-term use. Provided herein are methods and uses that meet such needs.Summary

[0004] Provided herein are methods and uses related to treatment using voclosporin. In some aspects, the methods and uses relate to administering voclosporin to subjects that have previously received a different calcineurin inhibitor (CNI), such as cyclosporin or tacrolimus or a derivative thereof, which in some cases are called legacy CNIs. Also provided are methods and uses related to selecting subjects treatment using voclosporin. In some aspects,the methods and uses relate to selecting subjects that have previously received a different CNI, such as cyclosporin or tacrolimus or a derivative thereof, which in some cases are called legacy CNIs. In some aspects, voclosporin is administered to the selected subjects.

[0005] Provided herein are methods of treatment that involve selecting a subject that has previously received a first CNI for immunosuppression for at least 30 days, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof; and administering voclosporin to the selected subject.

[0006] Also provided are methods of treatment that involve administering voclosporin to a subject that has previously received a first CNI for immunosuppression for at least 30 days, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

[0007] Also provided are methods for selecting a subject for treatment with voclosporin that involve selecting a subject that has previously received a first CNI for immunosuppression for at least 30 days, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

[0008] In some of any of the embodiments, the methods also involve performing one or more renal biopsies on the subject. In some of any of the embodiments, the one or more indicators of drug-induced nephrotoxicity is assessed based on the one or more renal biopsies.

[0009] Also provided are methods of reducing drug-induced nephrotoxicity that involve selecting a subject that exhibits one or more indicators of drug-induced nephrotoxicity after previously receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof; and administering voclosporin to the selected subject.

[0010] Also provided are methods of reducing drug-induced nephrotoxicity that involve administering voclosporin to a subject that exhibits one or more indicators of drug-induced nephrotoxicity after previously receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

[0011] Also provided are methods for selecting a subject for treatment with voclosporin that involve selecting a subject that exhibits one or more indicators of drug-induced nephrotoxicity after previously receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

[0012] In some of any of the embodiments, the one or more indicators of drug-inducednephrotoxicity is assessed based on one or more renal biopsies.

[0013] Also provided are methods of reducing drug-induced tubular dysfunction that involve selecting a subject that exhibits one or more indicators of drug-induced tubular dysfunction after previously receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof; and administering voclosporin to the selected subject.

[0014] Also provided are methods of reducing drug-induced tubular dysfunction that involve administering voclosporin to a subject that exhibits one or more indicators of drug- induced tubular dysfunction after previously receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

[0015] Also provided are methods for selecting a subject for treatment with voclosporin that involve selecting a subject that exhibits one or more indicators of drug-induced tubular dysfunction after previously receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

[0016] In some of any of the embodiments, the drug-induced tubular dysfunction comprises drug-induced hypercalcemia.

[0017] Also provided are methods of reducing drug-induced hypercalcemia that involve selecting a subject that exhibits one or more indicators of drug-induced hypercalcemia after previously receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof; and administering voclosporin to the selected subject.

[0018] Also provided are methods of reducing drug-induced hypercalcemia that involve administering voclosporin to a subject that exhibits one or more indicators of drug-induced hypercalcemia after previously receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

[0019] Also provided are methods for selecting a subject for treatment with voclosporin that involve selecting a subject that exhibits one or more indicators of drug-induced hypercalcemia after previously receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

[0020] In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits a 10% or greater increase in fractional calcium excretion asassessed after receiving the first CNI, compared to a baseline fractional calcium excretion as assessed prior to receiving the first CNI. In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits a 2-fold or greater increase in fractional calcium excretion as assessed after receiving the first CNI, compared to a baseline fractional calcium excretion as assessed prior to receiving the first CNI.

[0021] In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits a 1.2-fold or greater increase in fractional magnesium excretion as assessed after receiving the first CNI, compared to a baseline fractional magnesium excretion as assessed prior to receiving the first CNI.

[0022] In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits a 33% or greater decrease in urine epidermal growth factor normalized to creatinine (uEGF / Cr) as assessed after receiving the first CNI, compared to a baseline uEGF / Cr as assessed prior to receiving the first CNI.

[0023] In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits a 2-fold or greater decrease in the level of calbindin-D28K as assessed after receiving the first CNI, compared to a baseline level of calbindin-D28K as assessed prior to receiving the first CNI.

[0024] In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits a 1.5-fold or greater decrease in the level of sodiumchloride cotransporter (NCC) as assessed after receiving the first CNI, compared to a baseline level of NCC as assessed prior to receiving the first CNI.

[0025] In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits a 30% or greater decrease in the expression level of one or more genes selected from the group consisting of Slcl2a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8al, and Calbl, as assessed after receiving the first CNI, compared to a respective baseline expression level of the one or more genes as assessed prior to receiving the first CNI.

[0026] In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits hypercal ciuria.

[0027] In some of any of the embodiments, the drug-induced tubular dysfunction comprises hyperkalemia. In some of any of the embodiments, the hyperkalemia is identifiedby a serum potassium level of > 5 mmol / L.

[0028] In some of any of the embodiments, the drug-induced tubular dysfunction comprises hypomagnesemia. In some of any of the embodiments, the hypomagnesemia is identified by a serum magnesium level less than 1.4 mg / dL.

[0029] In some of any of the embodiments, the drug-induced tubular dysfunction comprises hypophosphatemia.

[0030] Also provided are methods of treatment that involve selecting a subject that exhibits a 10% or greater increase in fractional calcium excretion as assessed after receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline fractional calcium excretion assessed prior to receiving the first CNI; and administering voclosporin to the selected subject.

[0031] Also provided are methods for selecting a subject for treatment with voclosporin that involve selecting a subject that exhibits a 10% or greater increase in fractional calcium excretion as assessed after receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline fractional calcium excretion assessed prior to receiving the first CNI.

[0032] In some of any of the embodiments, the subject is selected for treatment if the subject exhibits a 20% or greater increase in fractional calcium excretion after receiving the first CNI.

[0033] Also provided are methods of treatment that involve selecting a subject that exhibits a 2-fold or greater increase in fractional calcium excretion as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline fractional calcium excretion as assessed prior to receiving the first CNI; and administering voclosporin to the selected subject.

[0034] Also provided are methods for selecting a subject for treatment with voclosporin that involve selecting a subject that exhibits a 2-fold or greater increase in fractional calcium excretion as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline fractional calcium excretion as assessed prior to receiving the first CNI.

[0035] In some of any of the embodiments, the subject is selected for treatment if the subject exhibits a 3-fold or greater increase in fractional calcium excretion after receiving the first CNI.

[0036] Also provided are methods of treatment that involve selecting a subject that exhibits a 1.2-fold or greater increase in fractional magnesium excretion as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline fractional magnesium excretion as assessed prior to receiving the first CNI; and administering voclosporin to the selected subject.

[0037] Also provided are methods for selecting a subject for treatment with voclosporin that involve selecting a subject that exhibits a 1.2-fold or greater increase in fractional magnesium excretion as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline fractional magnesium excretion as assessed prior to receiving the first CNI.

[0038] In some of any of the embodiments, the subject is selected for treatment if the subject exhibits a 1.5 -fold or greater increase in fractional magnesium excretion after receiving the first CNI.

[0039] Also provided are methods of treatment that involve selecting a subject that exhibits a 33% or greater decrease in urine epidermal growth factor normalized to creatinine (uEGF / Cr) as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline uEGF / Cr as assessed prior to receiving the first CNI; and administering voclosporin to the selected subject.

[0040] Also provided are methods for selecting a subject for treatment with voclosporin that involve selecting a subject that exhibits a 33% or greater decrease in urine epidermal growth factor normalized to creatinine (uEGF / Cr) as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline uEGF / Cr as assessed prior to receiving the first CNI.

[0041] In some of any of the embodiments, the subject is selected for treatment if thesubject exhibits a 40% or greater decrease in uEGF / Cr after receiving the first CNI.

[0042] Also provided are methods of treatment that involve selecting a subject that exhibits a 2-fold or greater decrease in the level of calbindin-D28K as as assessed after receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline level of calbindin-D28K as assessed prior to receiving the first CNI; and administering voclosporin to the selected subject.

[0043] Also provided are methods for selecting a subject for treatment with voclosporin that involve selecting a subject that exhibits a 2-fold or greater decrease in the level of calbindin-D28K as as assessed after receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline level of calbindin-D28K as assessed prior to receiving the first CNI.

[0044] In some of any of the embodiments, the subject is selected for treatment if the subject exhibits a 3-fold or greater increase in the level of calbindin-D28K after receiving the first CNI.

[0045] Also provided are methods of treatment that involve selecting a subject that exhibits a 1.5-fold or greater decrease in the level of sodium-chloride cotransporter (NCC) as as assessed after receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline level of NCC as assessed prior to receiving the first CNI; and administering voclosporin to the selected subject.

[0046] Also provided are methods for selecting a subject for treatment with voclosporin that involve selecting a subject that exhibits a 1.5-fold or greater decrease in the level of sodium-chloride cotransporter (NCC) as as assessed after receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline level of NCC as assessed prior to receiving the first CNI.

[0047] In some of any of the embodiments, the subject is selected for treatment if the subject exhibits a 2-fold or greater increase in the level of NCC after receiving the first CNI.

[0048] Also provided are methods of treatment that involve selecting a subject that exhibits a 30% or greater decrease in the expression level of one or more genes selected from the group consisting of Slcl2a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8al, and Calbl as assessedafter receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline expression level of the one or more genes as assessed prior to receiving the first CNI; and administering voclosporin to the selected subject.

[0049] Also provided are methods for selecting a subject for treatment with voclosporin that involve selecting a subject that exhibits a 30% or greater decrease in the expression level of one or more genes selected from the group consisting of Slcl2a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8al, and Calbl as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline expression level of the one or more genes as assessed prior to receiving the first CNI.

[0050] In some of any of the embodiments, the subject is selected for treatment if the subject exhibits a 50% or greater decrease in the expression level of the one or more genes after receiving the first CNI.

[0051] Also provided are methods of reducing drug-induced dyslipidemia that involve selecting a subject that exhibits one or more indicators of drug-induced dyslipidemia after previously receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof; and administering voclosporin to the selected subject.

[0052] Also provided are methods of reducing drug-induced dyslipidemia that involve administering voclosporin to a subject that exhibits one or more indicators of drug-induced dyslipidemia after previously receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

[0053] Also provided are methods for selecting a subject for treatment with voclosporin that involve selecting a subject that exhibits one or more indicators of drug-induced dyslipidemia after previously receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

[0054] In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits hypertriglyceridemia as assessed after receiving the first CNI. In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits a 30% or greater increase in the level of triacylglycerol(TAG), as assessed after receiving the first CNI, compared to a baseline level of TAG as assessed prior to receiving the first CNI.

[0055] In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits a 30% or greater increase in the level of ceramides (CER), as assessed after receiving the first CNI, compared to a baseline level of CER as assessed prior to receiving the first CNI.

[0056] In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits hypercholesterolemia as assessed after receiving the first CNI. In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits a 30% or greater increase in the level of low density lipoprotein (LDL) cholesterol, as assessed after receiving the first CNI, compared to a baseline level of LDL as assessed prior to receiving the first CNI.

[0057] Also provided are methods of treatment that involve selecting a subject that exhibits a reduction of blood levels of mycophenolic acid (MPA) after previously receiving a first CNI in combination with my cophenolate mofetil (MMF) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof; and administering voclosporin to the selected subject.

[0058] Also provided are methods of treatment that involve administering voclosporin to a subject that exhibits a reduction of blood levels of mycophenolic acid (MPA) after previously receiving a first CNI in combination with my cophenolate mofetil (MMF) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

[0059] Also provided are methods for selecting a subject for treatment with voclosporin that involve selecting a subject that exhibits a reduction of blood levels of mycophenolic acid (MPA) after previously receiving a first CNI in combination with my cophenolate mofetil (MMF) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

[0060] In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits a 1.5-fold or greater reduction in the blood levels of MPA, as assessed after receiving the first CNI, compared to a baseline blood level of MPA as assessed prior to receiving the first CNI. In some of any of the embodiments, the bloodlevels of MPA are determined as the maximum serum concentration (Cmax) or area under the concentration curve from time 0 to 12 h (AUC0-12).

[0061] Also provided are methods of reducing new-onset diabetes that involve selecting a subject that exhibits one or more indicators of new-onset diabetes after previously receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof; and administering voclosporin to the selected subject.

[0062] Also provided are methods of reducing new-onset diabetes that involve administering voclosporin to a subject that exhibits one or more indicators of new-onset diabetes after previously receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

[0063] Also provided are methods for selecting a subject for treatment with voclosporin that involve selecting a subject that exhibits one or more indicators of new-onset diabetes after previously receiving a first CNI for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

[0064] In some of any of the embodiments, the new-onset diabetes comprises new-onset diabetes after transplant (NODAT). In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits hyperglycemia. In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits islet cell death.

[0065] In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits interstitial fibrosis and tubular atrophy in observed in > 5% in cortical area after receiving the first CNI, based on the renal biopsies. In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits medial arteriolar hyalinosis after receiving the first CNI, based on the renal biopsies. In some of any of the embodiments, medial arteriolar hyalinosis is identified by the replacement of necrotic smooth muscle cells with focal, circular lumpy protein (hyaline) deposits at the periphery of the wall of afferent arterioles, and / or the narrowing of the vascular lumen. In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits glomerular injury medial arteriolar hyalinosis after receiving the first CNI, based on the renal biopsies. In some of any of the embodiments, glomerular injury is identified by global and segmental glomerulosclerosis, tubular atrophy, interstitial fibrosis, and / or arteriosclerosis are observed; and / or the total renal chronicity score of > 1. In some ofany of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits juxtaglomerular apparatus (JGA) after receiving the first CNI, based on the renal biopsies. In some of any of the embodiments, JGA hyperplasia is identified by enlargements of juxtaglomerular apparatus components comprising one or more of: the vascular components, the mesangial cell components, the tubular components (the macula densa); and / or the presence of intracellular renin granules. In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits tubular microcalcifications after receiving the first CNI, based on the renal biopsies. In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits a 10% or greater loss of P-gly coprotein (P-gp) expression as assessed after receiving the first CNI, compared to a baseline P-gp expression as assessed prior to receiving the first CNI, based on the renal biopsies. In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits a Drug-induced nephrotoxicity score of Nephrotoxicity Score of 0-3 after receiving the first CNI, based on the renal biopsies. In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits a Banff score of 0-3 after receiving the first CNI, based on the renal biopsies.

[0066] In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits an increase in the National Institutes of Health Activity Index (NIH-AI) from a renal biopsy as assessed after receiving the first CNI, compared to a baseline NIH-AI as assessed prior to receiving the first CNI, based on the renal biopsies. In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI of 3 or higher after receiving the first CNI, based on the renal biopsies.

[0067] In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits a 30% or greater increase in the National Institutes of Health Chronicity Index (NIH-CI) as assessed after receiving the first CNI, compared to a baseline NIH-CI as assessed prior to receiving the first CNI, based on the renal biopsies. In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits a 40% or greater increase in the NIH-CI, compared to the baseline NIH- CI, based on the renal biopsies. In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits a NIH-CI of 3 or higher after receivingthe first CNI, based on the renal biopsies.

[0068] In some of any of the embodiments, the subject is selected for administration of voclosporin if the subject exhibits a 10% or greater increase in a Tubulointerstitial Activity Index (TIAI) as assessed after receiving the first CNI, compared to a baseline TIAI, based on the renal biopsies.

[0069] In some of any of the embodiments, the subject has previously received cyclosporin, tacrolimus, or derivative thereof for at least 30 days. In some of any of the embodiments, the subject has previously received cyclosporin, tacrolimus, or derivative thereof for at least 30 days, at least 60 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days, at least 1 year, at least 1.5 years, at least 2 years, at least 2.5 years, at least 3 years, or longer.

[0070] In some of any of the embodiments, the first CNI comprises cyclosporin. In some of any of the embodiments, the first CNI comprises cyclosporine A.

[0071] In some of any of the embodiments, the first CNI comprises tacrolimus.

[0072] In some of any of the embodiments, the subject has previously received an organ transplant or is a candidate for an organ transplant.

[0073] In some of any of the embodiments, the subject has or has been diagnosed with a proteinuric kidney disease. In some of any of the embodiments, the subject has or has been diagnosed with lupus nephritis (LN).

[0074] In some of any of the embodiments, the methods also involve discontinuing the administration of the first CNI, before beginning the administration of the voclosporin.

[0075] In some of any of the embodiments, the methods also involve administering voclosporin to the selected subject.

[0076] In some of any of the embodiments, the voclosporin is administered at a daily dose of between about 5 mg BID to about 50 mg BID. In some of any of the embodiments, the voclosporin is administered at an initial daily dose of about 39.5 mg, about 31.6 mg, about 23.7 mg, about 15.8 mg, or about 7.9 mg BID. In some of any of the embodiments, the voclosporin is administered at an initial daily dose of about 39.5 mg. In some of any of the embodiments, the voclosporin is administered at an initial daily dose of about 23.7 mg. In some of any of the embodiments, the voclosporin is administered at an initial daily dose ofabout 15.8 mg.

[0077] In some of any of the embodiments, the voclosporin is administered over a projected voclosporin treatment period of at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 24 months, at least 36 months, or at least 48 months or longer.

[0078] In some of any of the embodiments, the methods also involve assessing the estimated Glomerular Filtration Rate (eGFR) of the subject at at least a first time point and a second time point on different days of the projected treatment period; and if the eGFR of the subject decreases by more than a target % to below a predetermined value, between the first and second time points, reducing the daily dose by increment(s) of 7.9 mg BID or stopping the administering of voclosporin; if the eGFR of the subject decreases by less than the target %, between the first and second time points, continuing administering the same predetermined daily dosage of voclosporin to the subject.

[0079] In some of any of the embodiments, the predetermined value is in the range of 50- 90 ml / min / 1.73m2. In some of any of the embodiments, the predetermined value is approximately 60 ml / min / 1.73m2.

[0080] In some of any of the embodiments, the target % is in the range of 20%-45%. In some of any of the embodiments, the target % is approximately 30%.

[0081] In some of any of the embodiments, if the eGFR of the subject decreases by >30% to a value of below 60 mL / min / 1.73m2between the first and second time points, stopping the administering of voclosporin to the subject; if the eGFR of the subject decreases by between 20% to 30% to a value of below 60 ml / min / 1.73m2between the first and second time points, administering a reduced dosage of voclosporin to the subject; and if the eGFR of the subject decreases by <20% between the first and second time points, continuing administering the same predetermined daily dosage of voclosporin to the subject.

[0082] In some of any of the embodiments, the first time point is immediately preceding initiating the administration of voclosporin. In some of any of the embodiments, the second time point is after the first time point and initiating the administration of voclosporin. In some of any of the embodiments, the second time point is 8 weeks after initiating the administration of voclosporin.

[0083] In some of any of the embodiments, the methods also involve determining theeGFR of the subject at a third time point and if the eGFR is determined at the third time point to differ from the eGFR determined at the first time point by less than the target %, resuming administering the predetermined daily dosage of voclosporin.

[0084] In some of any of the embodiments, the methods also involve measuring urinary protein creatinine ratio (UPCR) of the subject at the first time point and the second time point and determining any reduction of the UPCR between the first and second time points, and if the UPCR of the subject fails to show a reduction of at least 25% at the second time point, discontinuing administering voclosporin to the subject.

[0085] In some of any of the embodiments, the methods also involve measuring the concentration of C3 or C4 in the blood of the subject at the first time point and the second time point, and determining whether the concentration of C3 or C4 is normalized at the second time point, and if normalization of C3 or C4 is found, reinstating the administering voclosporin to the subject.

[0086] In some of any of the embodiments, the methods also involve administering to the subject an effective amount of my cophenolate mofetil (MMF).

[0087] In some of any of the embodiments, the methods also involve administering to the subject an effective amount of a corticosteroid.

[0088] In some of any of the embodiments, the voclosporin is a mixture of at least 90% E isomer and not more than 10% Z isomer.

[0089] Also provided herein is voclosporin for use in any of the provided methods.

[0090] Also provided herein are uses of voclosporin in the manufacture of a medicament in accordance with any of the provided methods.

[0091] Also provided herein are uses of voclosporin in any of the provided methods.Brief Description of the Drawings

[0092] FIG. 1 shows a schematic representation of a trial comparing the safety and efficacy of voclosporin to placebo at 24 and 48 weeks in subjects concurrently administered my cophenolate mofetil (MMF) and oral corticosteroids (top panel), of whom were subject to the presented tapering protocol (bottom panel).

[0093] FIG. 2 shows a schematic representation of the long-term safety and tolerability continuation study. As depicted, 216 subjects out of the 357 subjects who were included inthe initial 1-year study continued on to the continuation study. Time points for baseline and repeat biopsies are also shown for the subgroup of subjects.

[0094] FIG. 3 shows the mean estimated glomerular filtration rates (eGFR) for the 116 subjects in the voclosporin group and the 100 subjects in the control group over a period of 36 months with an additional 4-week follow-up time point. The number of subjects in each study arm over the same time points is also depicted.

[0095] FIG. 4 shows the mean corrected estimated glomerular filtration rates (eGFR; 95% Confidence Interval) as well as the mean change from pretreatment baseline in corrected eGFR for the 116 subjects in the voclosporin group and the 100 subjects in the control group over a period of 36 months, with an additional 4-week follow-up time point. The number of subjects in each study arm at the same time points is also depicted. Pretreatment baseline was defined as the last value before subject received first dose of study drug on Day 1 of the initial 12 months study (e.g., at the beginning of the 36 months).

[0096] FIG. 5 shows the mean corrected estimated glomerular filtration rates (eGFR) slope and eGFR change (95% Confidence Interval) from Month 12 for the 116 subjects in the voclosporin group and the 100 subjects in the control group over a period of 24 months (i.e., Month 12 to Month 36). Mean corrected eGFR slope and eGFR change are calculated from entry into the continuation study (month 12 of treatment) to the end of the continuation study (month 36 of treatment). The number of subjects in each study arm at the same time points is also depicted.

[0097] FIG. 6 shows the mean UPCR (mg / mg) for the 116 subjects in the voclosporin and the 100 subjects in the control group over a period of 36 months, with an additional 4- week follow-up time point. The number of subjects in each study arm at the same time points is also depicted.

[0098] FIG. 7 shows the proportion of subjects with 50% reduction in UPCR at every 6 months for a duration of 36 months, and includes the additional 4-week follow up time point. The number of subjects in each study arm at the same time points is also depicted.

[0099] FIG. 8 shows the mean urine protein creatinine ratio (UPCR) over a 3-year study for the subgroup of 26 subjects (16 in the voclosporin group and 10 in the control group) who were assessed by repeat renal biopsies, and the 357 total study subjects evaluated in the study.

[0100] FIG. 9 shows the mean estimated glomerular filtration rates (eGFR) over a 3-year study for the subgroup of 26 subjects (16 in the voclosporin group and 10 in the control group) who were assessed by repeat renal biopsies, and the 357 total study subjects evaluated in the study.

[0101] FIG. 10 shows the least squares mean corrected estimated glomerular filtration rate (eGFR) over a 3-year study for the subgroup of 26 subjects (16 in the voclosporin group and 10 in the control group) who were assessed by repeat renal biopsies, and the subjects of the larger total study group for the 2-year continuation study (n = 216). Renal function was assessed with corrected eGFR (Chronic Kidney Disease Epidemiology Collaboration equation) using a prespecified ceiling of 90 mL / min / 1.73 m2

[0102] FIG. 11A-FIG. 11B are box plots depicting disease activity (FIG. 11 A; as assessed based on renal biopsies assessing the National Institutes of Health Activity Index - NIH-AI; scale 0-24) and chronicity (FIG. 11B; as assessed based on renal biopsies assessing the National Institutes of Health Chronicity Index - NIH-CI; scale 0-12) over a 3-year study for the subgroup of 26 subjects (16 in the voclosporin group and 10 in the control group), assessed at baseline (BL) and a follow-up (approximately 18 months after treatment with voclosporin). The symbol “x” represents mean and the horizontal bold line represents median. The top and bottom boxes represent the 75thand 25thpercentiles. Outliers are represented as individual dots.

[0103] FIG. 12A depicts fractional calcium excretion in terms of fold change, relative to the vehicle control, from animals that received daily injections of either tacrolimus or voclosporin. FIG. 12B depicts fractional magnesium excretion in terms of fold change, relative to the vehicle control, from animals that received daily injections of either tacrolimus or voclosporin. FIG. 12C show plasma magnesium levels, in terms of nmol / L, and FIG. 12D depict urine epidermal growth factor normalized to creatinine (uEGF / Cr) in terms of pg / mmol, from animals that received a vehicle, tacrolimus or voclosporin injection.

[0104] FIG. 12E depicts fractional sodium excretion in terms of fold change, relative to the vehicle control, from animals that received daily injections of either tacrolimus or voclosporin. FIG. 12F depicts fractional chloride excretion in terms of fold change, relative to the vehicle control, from animals that received daily injections of either tacrolimus or voclosporin. Calculated values are normalized to the mean values of the vehicle group defined as 1.0. Shown are data points with mean ± SD (* P < 0.05; ** P < 0.01; *** P <0.001; N.S., not significant; one-way ANOVA with Dunnetf s T3 post hoc testing).

[0105] FIG. 12G shows immunoblotting of whole kidney homogenates for sodiumchloride cotransporter (NCC)-total, calbindin-D28K, calcium channel TRPV5, calcium channel TRPM6, and GAPDH (control) from animals that received daily intraperitoneal injections of a vehicle, tacrolimus, or voclosporin. FIG. 12H depicts the densitometric analysis of the immunoblots. Relative protein abundance (mean ±are shown relative to the vehicle group (defined as 1.0) as band intensities are normalized to the mean intensity of the vehicle group. ** is P < 0.01 vs. vehicle; *** is P <0.001 vs. vehicle.

[0106] FIG. 121 shows immunoblotting of whole kidney homogenates for sodiumchloride cotransporter (NCC)-total, pNCC-T53 (phosphorylated at threonine 53), calbindin- D28K, and sodium-calcium exchanger NCX1, and GAPDH (control) from animals that received daily intraperitoneal injections of a vehicle, tacrolimus, or voclosporin. FIG. 12 J depicts the densitometric analysis of the immunoblots shown in FIG. 121 as well as of additional immunoblots not shown in FIG. 121. Band intensities are normalized to GAPDH and to the mean intensity of the vehicle group defined as 1.0. Values displayed are mean ± SD (one-way ANOVA with Dunnetf s T3 post hoc test).

[0107] FIG. 12K shows the relative mRNA expression levels of the solute carrier family 12 member A3 (Slcl2a3) gene, the transient receptor potential cation channel subfamily M Member 6 (Trpm6) gene, the cyclin and CBS domain divalent metal cation transporter mediator 2 (Cnnm2) gene, the epidermal growth factor (Egf) gene, the calcium channel TRPV5 gene, the solute carrier family 8 member Al (Slc8Al) gene and the calbindin 1 (Calbl) gene in either tacrolimus or voclosporin treated animals, relative to the expression levels shown in vehicle control animals. Gene expression was normalized to Actb and to mean values of the vehicle group defined as 1.0. Shown are data points with mean ± SD (* P < 0.05; ** P < 0.01; *** P < 0.001; N.S., not significant; one-way ANOVA with Dunnetf s T3 post hoc testing, except for Cnnm2 and Trpv5 by Kruskal -Wallis test).

[0108] FIG. 12L shows the natriuretic response to hydrochlorothiazide at day 20. FIG. 12M shows the chloruretic response to hydrochlorothiazide at day 20. The natriuretic and chloriuretic responses shown depict the 6-hour response of a single dose of hydrochlorothiazide (25 mg / kg i.p.) on A urinary Na+and Cl’ excretion, respectively. Values displayed are mean ± SD (one-way ANOVA with Dunnetf s T3 post hoc test; A, thiazide - vehicle; data obtained on day 19 for vehicle and on day 20 for thiazide). * P < 0.05; ** P <0.01; *** P < 0.001; N.S., not significant.

[0109] FIGS. 12N and 120 demonstrate the effects of tacrolimus and voclosporin on endothelin-1 and cyclo-oxygenase-2 (COX-2) after 28 days of treatment. FIG. 12N depicts plasma endothelin-1 (pg / ml). FIG. 120 depicts relative COX-2 mRNA expression. Gene expression was normalized to Actb and to mean values of the vehicle group defined as 1.0. Shown are data points with mean ± SD (one-way ANOVA with Dunnett’s T3 post hoc testing for endothelin-1 and one-way ANOVA with Kruskal -Wallis test for COX-2 mRNA).* P < 0.05; ** P < 0.01; *** P < 0.001; N.S., not significant.

[0110] FIG. 13A-FIG. 13C show insulin secretion from human islets treated with peak and trough concentrations of VCS and TAC. FIG. 13A shows averaged traces of dynamic insulin secretion measurements in the context of 3 mM glucose, 15 mM glucose, or 30 mM KC1 (as indicated). FIG. 13B shows the total area under the curve (AUC) for the 15 mM glucose response. FIG. 13C shows the total AUC for the KC1 response.

[0111] FIG. 14 shows the extent of islet cell survival from dispersed human islets treated with VCS and TAC. The plot shown is the maximum cell death normalized measurement for each condition TAC and VCS dose, normalized to the DMSO control cultures. Results shown are quantified from 5 cultures per drug condition, over 2 separate runs.

[0112] FIG. 15 shows the results of RNA sequencing analysis of human islets treated with TAC and VCS at peak doses. mRNAs that were nominally differentially expressed (adjusted P < 0.05) are shown.

[0113] FIG. 16 shows the mean (± standard deviation) plasma concentration of MPA after administration of MMF alone (Day 1) and in the presence of voclosporin (Day 7).

[0114] FIG. 17 shows the mean (± standard deviation) plasma concentration of MP AG after administration of MMF alone (Day 1) and in the presence of voclosporin (Day 7).

[0115] FIG. 18 shows MALDI-MSI imaging of cyclosporine (CsA), tacrolimus (TAC), or voclosporin (VCS) in a mouse kidney after IV administration of any of the three CNI. Mass to signal ratio is visualized as color intensity maps (m / z intensity) to provide spatial information for the detected molecules.

[0116] FIG. 19A-FIG. 19K show the structure of various voclosporin metabolites. FIG. 19A shows voclosporin metabolite IM4n. FIG. 19B shows voclosporin metabolite IM9, the primary metabolite. FIG. 19C shows voclosporin metabolite IMlc (R). FIG. 19D showsvoclosporin metabolite IMlc (S). FIG. 19E shows voclosporin metabolite IM19 (MeBmt: Cyclization). FIG. 19F shows voclosporin metabolite IM19. FIG. 19G shows voclosporin metabolite IM4. FIG. 19H shows voclosporin metabolite IMl-Diol-1. FIG. 191 shows voclosporin metabolite IMl-Diol-2. FIG. 19 J shows voclosporin metabolite IMl-Diol-3, a diastereomer of IMl-Diol-2 differing in configuration at the l-i] carbon of the aa-1. FIG. 19K shows a hypothetical voclosporin metabolite with trihydroxylation.

[0117] FIG. 20 shows MALDI-MSI imaging of cyclosporine A (“CsA”), voclosporin (“VSP”), and their metabolites in a mouse kidney after IV administration of either parent drug. Mass to signal ratio is visualized as color intensity maps (m / z intensity) to provide spatial information for the detected molecules.

[0118] FIG. 21A-FIG. 21E show a series of overlaid and separate in situ MALDI-MSI images for cyclosporine A (“CsA”) or voclosporin (“VSP”) parent drug and its metabolites in a mouse kidney following administration. FIG. 21A shows an overlaid image of cyclosporine A [CsA+Na]+and voclosporin metabolite [VSP+Na]+along with separate images for each parent drug. FIG. 21B shows overlaid and separate images for CsA metabolite [AM4n+Na]+and VSP metabolite [IM4n+Na]+. FIG. 21C shows overlaid and separate images for CsA metabolite [AMl / AMlc / AM9+Na]+and VSP metabolite [IMlc / IM4 / IM9+Na]+. FIG. 21D shows overlaid and separate images for CsA metabolite [AM19 / AMlc9+Na]+and VSP metabolite [IM19 (Cyclic)+Na]+. FIG. 21E shows overlaid and separate images for CsA metabolite [AM19 / AMlc9+Na]+and VSP metabolite [IM1- Diol-1 / IM19+Na]+. Mass to signal ratio is visualized as color intensity maps (m / z intensity) to provide spatial information for the detected molecules.

[0119] FIG. 22A shows the viability HEK293 cells plated on plastic labware when treated with various doses of CsA, Tac or Vcs at different time points. Error bars illustrate SEM (n=6). *: p < 0.05 versus control (CTL). FIG. 22B shows the viability of HEK293 cells plated on glass or plastic labware when treated with various doses of CsA, Tac or Vcs. Error bars illustrate SEM (n=3). FIG. 22C shows the inhibition of calcineurin phosphatase activity in HEK293 cells when treated with different doses of CsA, Tac or Vcs. Error bars illustrate SEM (n=6). *: p < 0.05 versus control.

[0120] FIG. 22D shows the expression of calcineurin isoforms in wild-type (WT) HEK293 compared to calcineurin a isoform PPP3CA KO (aKO) and calcineurin beta isoform PPP3CB KO ( KO) HEK293 cell lines. Anti-PPP3CA and anti-PPP3CB antibodiesspecific to the a and f> isoforms, respectively, were used for detection. -actin and GAPDH were used as loading controls. FIG. 22E shows the relative calcineurin protein expression across WT, aKO or KO HEK293 cell lines. Error bars illustrates SEM (n=3). *: p < 0.05 versus WT control. FIG. 22F shows the inhibition of calcineurin phosphatase activity in WT, aKO or KO HEK293 cell lines cell lines when treated with various concentrations of CsA, Tac or Vcs. Error bars illustrates SEM (n=5). *: p < 0.05 versus control.A: p < 0.05 versus WT control.

[0121] FIG. 22G shows a Western blot for downstream calcineurin targets MMP-9 and Smadl in WT, aKO or KO HEK293 cell lines when treated with 20 pM of CsA, Tac or Vcs. FIG. 22H shows a quantification of the protein expression of downstream targets MMP-9 and Smadl in WT, aKO or KO HEK293 cell lines when treated with 20 pM of CsA, Tac or Vcs. Error bars illustrate SEM (n=2).Detailed Description

[0122] Provided herein are methods of treatment and selecting subjects for treatment, and uses such as therapeutic uses of voclosporin, that involves selecting subjects that have previously received a different calcineurin inhibitor (CNI), such as cyclosporin or tacrolimus or a derivative thereof, as an immunosuppressant. In some aspects, the methods and uses also involve administering voclosporin to the selected subjects. In some aspects, voclosporin is administered to the selected subjects.

[0123] Legacy CNIs, such as cyclosporin (including derivatives of cyclosporin, such as cyclosporine A (CsA)) and tacrolimus (TAC), or derivatives thereof, are potent immunosuppressants, and have been tested for the treatment of a variety of conditions that typically require long-term immunosuppression, including use in conjunction with organ or tissue transplant. The legacy CNI compounds in some contexts have been associated with adverse effects, side effects or toxicities, such as drug-induced nephrotoxicity. There is a need for a CNI that is tolerated long-term or can be used for prolonged administration, with reduced or minimal risk of adverse effects or toxicities. In some aspects, subjects who have previously been administered a legacy CNI, particularly for a prolonged time, are at risk of or have already developed one or more indicators of the adverse effect or toxicity.

[0124] In some aspects, in the provided methods, protocols, treatment regimens and / or uses, such as therapeutic uses, subjects who have previously received a first CNI is selectedfor administration of voclosporin. In some aspects, provided embodiments involve switching from the use of a legacy CNI (such as cyclosporin, tacrolimus or derivatives thereof; in some aspects referred to a “traditional CNI,” a “first-generation CNI”, or a “first CNI” in the present disclosure) to voclosporin, as an immunosuppressant. In some aspects, the provided embodiments permit the long-term use of a CNI (voclosporin) while avoiding drug-induced nephrotoxicity and other clinical issues, for example, in the treatment of proteinuric kidney disease, such as lupus nephritis (LN), or associated with a transplant. In some embodiments, the CNI that is administered to the selected subject is voclosporin. In some aspects, the provided embodiments are based on an observation that unlike cyclosporine or tacrolimus, voclosporin does not require a need for therapeutic drug monitoring. In some embodiments, the disclosure involves switching the administration of a legacy CNI to voclosporin in a subject that needs administration of CNI for a prolonged period of time, who is susceptible to or has an increased risk of acute or chronic drug-induced nephrotoxicity or other adverse effects of CNI administration. In some aspects, the individual requires immunosuppression therapy and presents one or more risk factors for the development of calcineurin inhibitor nephrotoxicity.

[0125] In some aspects, the provided methods and uses are based on an observation that treatment with voclosporin in a subject who is in need of CNI therapy, such as a subject with lupus nephritis or a subject who has received or is a candidate of an organ or tissue transplant, results in safe and effective treatment, without a substantial increase in susceptibility to or risk of drug-induced nephrotoxicity or development of many of the clinical issues associated with legacy CNIs. Voclosporin has been shown to have higher rates of remission and response over three years in clinical trials against standard of care treatment while preserving renal function without the clinical manifestation of toxicities shown with legacy CNIs. In some aspects, the results provided herein support that treatment with voclosporin as an immunosuppressant does not have a substantial impact on certain drug-induced adverse effects or toxicities that can be associated with legacy CNIs, for example, on the concentrations of urinary electrolytes and / or lipids in the subject. In some aspects, as observed herein, the use of legacy CNI can be associated with adverse effects or toxicities tubular dysfunction and impact on electrolytes, such as hypomagnesemia and hyperkalemia, dyslipidemia, increase in inflammatory lipids, drug-drug interaction, and glucose dysregulation, such as hyperglycemia or new-onset diabetes, whereas voclosporin does not show such adverse effects or toxicities or shows a reduction of such adverse effects ortoxicities.

[0126] The provided methods and uses are also based on an observation, for example from imaging studies, that voclosporin and its metabolites do not accumulate at high concentrations in the kidney, whereas cyclosporine or tacrolimus, legacy CNIs, and their metabolites, accumulate in high concentrations, especially in the cortex. In some aspects, the results provided herein support that treatment with voclosporin does not result in glucose dysregulation and diabetes development that is associated with legacy CNIs. In some aspects, the results provided herein support that treatment with voclosporin is associated with a favorable metabolic profde with regard to lipids and glucose.

[0127] In some aspects, voclosporin also has been observed to have reduced drug-drug interactions with other drugs or immunosuppressants that are commonly administered together with a CNI, for example, my cophenolate mofetil (MMF) or its active moiety mycophenolic acid (MPA). In some aspects, co-administration of cyclosporine A (CsA) is associated with a reduction in blood MPA concentrations and discontinuation of CsA leads to MPA-related side effects such as leukopenia. In contrast, voclosporin was observed to have no clinically relevant effect on blood levels of MPA.

[0128] In addition, voclosporin provides an advantage that it has a higher affinity for calcineurin. Voclosporin can also distribute into organs, such as the lungs, in higher concentrations than in blood, and higher concentrations are found in red blood cells.

[0129] As described further herein, voclosporin provides multiple advantages over the legacy CNIs, particularly for subjects who have been administered a legacy CNI such as cyclosporin or tacrolimus. The results described herein support the advantages of using or switching to voclosporin, and the methods, treatment regimen, protocols and uses provided herein, for subjects who are in need of CNI therapy, particularly for subjects who have received legacy CNIs and are at risk of or have exhibited one or more indicators of drug- induced adverse effects or toxi cities.

[0130] In some aspects, the results support the benefit of switching a subject from administration of a legacy CNI, such as cyclosporin or tacrolimus, to voclosporin, especially for prolonged immunosuppression. Advantages and benefits include avoiding futile medication and unnecessary exposure to potential side effects from immunosuppressant treatment. Such advantages are particularly critical subjects who are at risk of adverse effects or toxicities, because immunosuppressant treatment regimens typically are long-term, andmany of the immunosuppressants are associated with undesirable side effects. Accordingly, voclosporin can be administered to the subjects for much longer period of time in these subjects, compared to traditional or legacy CNIs. Voclosporin also was observed to have a surprisingly high drug persistency. At about 24 months after the approval of voclosporin for the treatment of lupus nephritis (LN), approximately 26% of the subjects have remained on voclosporin treatment ,as estimated based on patient databases, which was substantially higher than the projected rate. These observations support that voclosporin can be used as a long-term immunosuppressant, instead of traditional or legacy CNIs. A subject who has received traditional or legacy CNIs would benefit in many respects from using voclosporin as an immunosuppressant.

[0131] All publications, including patent documents, scientific articles and databases, referred to in this application are incorporated by reference in their entirety for all purposes to the same extent as if each individual publication were individually incorporated by reference. If a definition set forth herein is contrary to or otherwise inconsistent with a definition set forth in the patents, applications, published applications and other publications that are herein incorporated by reference, the definition set forth herein prevails over the definition that is incorporated herein by reference.

[0132] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.I. METHODS OF TREATMENT AND USES OF VOCLOSPORIN

[0133] Provided herein are methods of treatment and uses involving selecting a subject who was previously administered a first calcineurin inhibitor (CNI) that is a legacy CNI, such as cyclosporin, tacrolimus or derivative thereof, and administering voclosporin to the subject. In some aspects, also provided are uses of voclosporin or compositions comprising voclosporin in accordance with any of the methods described herein. Uses include uses of voclosporin in such methods and treatments, and in the preparation of a medicament in order to carry out such methods. In some embodiments, the methods are carried out by selecting a subject previously administered a first CNI, such as cyclosporin, tacrolimus or derivative thereof, and administering voclosporin to the selected subject. In some aspects, the subject has previously received a first CNI for immunosuppression for at least 30 days. In some aspects, the subject exhibits one or more indicators of adverse effects or toxi cities associated with the first CNI, such as drug-induced nephrotoxicity, drug-induced hypercalcemia, drug-induced dyslipidemia, new onset diabetes, drug-drug interaction with other immunosuppressants, after previously receiving a first CNI. In some aspects, the provided methods and uses involve administration of an effective amount of voclosporin to a subject who has previously been administered a first CNI for purposes of immunosuppression.

[0134] In some embodiments, the method of treatment involves selecting a subject who has previously received a first CNI, such as cyclosporin, tacrolimus, or a derivative thereof for immunosuppression, for administration of voclosporin. In some embodiments, the method involves discontinuing the administration of cyclosporin, tacrolimus, or a derivative thereof. In some embodiments, the method involves administering a therapeutically effective amount of voclosporin to the selected subject who previously received a first CNI, such as cyclosporin, tacrolimus or a derivative thereof for immunosuppression. In some aspects, the provided embodiments involve selecting subjects who exhibit one or more indicators of drug- induced toxi cities or adverse effects from previous administration of the first CNI. In some aspects, the selection of subjects for administration of voclosporin is based on any of the criteria or assays described herein, for example in Section II. In some aspects, the subject is selected for voclosporin based on a renal biopsy.

[0135] In some embodiments, a subject previously administered a first CNI (such as cyclosporin or tacrolimus) is selected, the administration of the first CNI is discontinued, and the subject is administered voclosporin. In some aspects, voclosporin is based on any of the methods or treatment regimen described herein, for example in Section III.A. Immunosuppression with a First Calcineurin Inhibitor (CNI)

[0136] In some embodiments, the subject to be treated in accordance with the methods and uses provided herein include subjects in need of immunosuppression. In some aspects, the subject has received an agent for immunosuppression, such as a legacy CNI such as cyclosporin, tacrolimus or derivative thereof, for example for an extended period. In many cases, immunosuppressants need to be administered for a prolonged period of time, for example, for autoimmune diseases or due to an organ or tissue transplant. In some aspects, the subject is in need of immunosuppression, for example, the subject is an organ transplant recipient, is a candidate for an organ transplant, has a condition associated with transplant rejection, or has an autoimmune disease.

[0137] In some aspects, the provided methods and uses involve selecting subjects whohave received a first CNI, and administering voclosporin to the selected subjects. In some aspects, the subject has received a legacy CNI, such as cyclosporin, tacrolimus or derivative thereof, as an immunosuppressant, prior to being selected for administration of voclosporin. I n some embodiments, the first CNI is a legacy CNI, a first-generation CNI, or a traditional CNI.

[0138] In some embodiments, the subject to be treated in accordance with the methods and uses provided herein include subjects in need of immunosuppression, for example, due to a risk of transplant rejection. In some aspects, the subject is a candidate for a transplant, such as an organ transplant, a tissue transplant or a cell transplant. In some embodiments, the subject has received a heart, lung, liver, kidney, pancreas, skin, bowel, or cornea transplant. In some embodiments, the subject is a candidate for heart, lung, liver, kidney, pancreas, skin, bowel, or cornea transplant. In some aspects, the subject is a candidate for a transplant, such as an organ transplant, a tissue transplant or a cell transplant, and the subject is in need of immunosuppression. In some embodiments, the subject is a kidney transplant recipient (KTR). In some embodiments, the subject is a candidate for a kidney transplant.

[0139] In some embodiments, the subject has a condition associated with transplant rejection. In some embodiments, the condition is associated with heart, lung, liver, kidney, pancreas, skin, bowel, or cornea transplant rejection. In some embodiments, the condition is associated with heart transplant rejection. In some embodiments, the condition is associated with lung transplant rejection. In some embodiments, the condition is associated with liver rejection. In some embodiments, the condition is associated with kidney transplant rejection. In some embodiments, the condition is associated with pancreas transplant rejection. In some embodiments, the condition is associated with skin transplant rejection. In some embodiments, the condition is associated with bowel transplant rejection. In some embodiments, the condition is associated with cornea transplant rejection.

[0140] In some aspects, the subject has received an immunosuppressant treatment, such as a first CNI such as a legacy CNI, for example cyclosporin, tacrolimus or derivative thereof, associated with a transplant. In some aspects, the subject has received a first CNI in association with a transplant, during a first CNI treatment period which can begin before receiving the transplant or after receiving the transplant. In some embodiments, the subject has received a first CNI during a first CNI treatment period starting at before the transplant and ending at after the transplant. In some embodiments, the subject has received a first CNIduring a first CNI treatment period starting at after the transplant and ending at after the transplant.

[0141] In some embodiments, the subject has an autoimmune disease. Examples of autoimmune diseases include, without limitation, autoimmune hematological disorders (including e.g. hemolytic anemia, aplastic anemia, pure red cell anemia and idiopathic thrombocytopenia), systemic lupus erythematosus (SLE), lupus nephritis (LN), polychondritis, sclerodoma, ANCA vasculitis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Steven-Johnson syndrome, idiopathic sprue, (autoimmune) inflammatory bowel disease (including e.g. ulcerative colitis and Crohn’s disease), endocrine ophthalmopathy, Graves disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes (diabetes mellitus type I), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial lung fibrosis, psoriatic arthritis, glomerulonephritis (with and without nephrotic syndrome, e.g. including idiopathic nephrotic syndrome or minimal change nephropathy) and juvenile dermatomyositis. In some embodiments, the subject has or is at risk of systemic lupus erythematosus (SLE). In some embodiments, the subject has or is at risk of lupus nephritis (LN).

[0142] In some embodiments, the subject is in need of administration of an immunosuppressant for an extended period of time. In some aspects, immunosuppressants, such as a CNI, are required to be administered for an extended period of time. For example, certain treatment guidelines for diseases such as lupus nephritis, published by medical and scientific associations recommend immunosuppressants to be administered for at least for 6 months as an “induction” treatment, and the administration can be expected to last 3 years or more as “maintenance” treatment (see, e.g., “data show good results for induction therapy with MMF of 3 gm total dose daily for 6 months, followed by maintenance with lower doses of MMF for 3 years”, Hahn et al., Arthritis Care & Research 2012, 64(6):797-808). In some aspects, the subject is in need of administration of an immunosuppressant for at least 1 month, at least 3 months, at least 6 months, at least 1 year, or longer, for example, for more than 5 years.

[0143] In some aspects, the methods and uses involve selecting subjects who have previously received a first CNI that is a “legacy CNI” (in some cases also called a “traditional CNI” or a “first-generation CNI”, such as cyclosporin, tacrolimus or a derivative thereof). In some aspects, the methods involve selecting subjects who exhibit one or more indicators ofadverse effects, side effects or toxicities that are associated with the first CNI, such as drug- induced nephrotoxicity, new-onset diabetes, drug-induced dyslipidemia, or drug-drug interaction with other drugs used in combination. In some aspects, the subject is selected based on one or more criteria related to the one or more indicators. In some aspects, the methods and uses involve discontinuing the administration of the first CNI, and administering voclosporin to the selected subjects. In some aspects, also provided are methods and uses that relate to treating or reducing drug-induced nephrotoxicity, drug-induced tubular dysfunction, drug-induced hypercalcemia, new-onset diabetes, drug-induced dyslipidemia, as well as reducing chronic drug-induced nephrotoxicity. Also provided are uses, such as therapeutic uses, of voclosporin in accordance with any of the provided methods.

[0144] In some aspects, the subjects include subjects who have received administration of the first CNI that is a legacy CNI, such as cyclosporin, tacrolimus or a derivative thereof. In some aspects, the subject is in need of immunosuppression, such as long-term or extended immunosuppression, for example, for at least several months or years. In some aspects, first CNI has been administered for immunosuppression to treat diseases or conditions such as an autoimmune disease including systemic lupus erythematosus (SLE), lupus nephritis (LN) or psoriasis; or to a subject who has received or is a candidate for receiving an organ or tissue transplant.

[0145] CNIs are used as immunosuppressants for subjects suffering from a variety of conditions, particularly those conditions that include an autoimmunity component to the pathology. The immunosuppressant activity of CNIs is thought to help treat the direct causes of symptoms of conditions associated immune system activity. For example, CNIs are used as part of treatment for transplantation, either alone or with other medications, to prevent transplant rejection particularly in subjects receiving kidney, liver, and heart transplants.CNIs are also used alone or with methotrexate to treat rheumatoid arthritis or psoriasis. CNIs are also used to treat lupus nephritis.

[0146] The immunosuppressive properties of CNIs such as cyclosporin and tacrolimus are thought to result from inhibition of calcineurin, a phosphatase. Calcineurin is a key enzyme involved in T cell activation and proliferation. Cyclosporin and tacrolimus are thought to inhibit the phosphatase activity of calcineurin. This inhibition in turn suppresses IL-2 production, and thus T cell activation. For many of the immunosuppressants, including CNIs, they need to be administered for an extended period of time, such as at least 1 month,at least 3 months, at least 6 months, at least 1 year, or longer, for example, for more than 5 years.

[0147] In some aspects, the first CNI is cyclosporin or a derivative thereof. In some aspects, the legacy CNI is cyclosporin or a derivative thereof. In some aspects, the legacy CNI is cyclosporin. In some aspects, the legacy CNI is cyclosporine A (CsA). Cyclosporin (in some cases called cyclosporine or ciclosporin) and derivatives of cyclosporin, such as cyclosporine A (CsA), have been a front line CNI used for immunosuppression related to transplant. Although cyclosporine A and voclosporin are structurally similar, the two compounds display different metabolic stability and distribution, and certain metabolites of cyclosporine A have been correlated with nephrotoxicity (Wu and Kuca, Current Drug Metabolism 2019;20(2): 84-90(7)). In some aspects, the subject is selected for administration of voclosporin if the subject has previously received cyclosporin or a derivative thereof for immunosuppression. In some aspects, the subject is selected for administration of voclosporin if the subject has previously received cyclosporine A (CsA) for immunosuppression.

[0148] In some aspects, the first CNI is tacrolimus (TAC). In some aspects, the legacy CNI is tacrolimus (TAC) or a derivative thereof. In some aspects, the legacy CNI is tacrolimus. Tacrolimus has also been used successfully for immunosuppression related to transplant. Both cyclosporine and tacrolimus were first introduced for solid organ transplantation in the 1980s and are considered legacy CNIs or traditional, first -generation CNI. Currently, the majority of KTRs have a CNI-based regimen as standard maintenance immunosuppression with a preference for tacrolimus over cyclosporine (including derivatives such as cyclosporine A (CsA)) because of tacrolimus’ superiority on long-term renal graft function, allograft survival, and acute rejection rates (Ekberg et al.. N Engl J. Med. 2007, 357(25):2562-75; Hariharan et al., N Engl J Med. 2021 Aug 19; 385(8):729-743). In some aspects, the subject is selected for administration of voclosporin if the subject has previously received tacrolimus or a derive thereof for immunosuppression.B. Adverse Effects or Toxicities

[0149] Unfortunately, long term administration of legacy CNIs can lead to adverse effects or toxicities. For example, in patients with glomerulonephropathy (such as, but not limited to, lupus nephritis) legacy CNI administration can lead to additional acute or chronic drug- induced nephrotoxicity. Long-term use of legacy CNI such as cyclosporin, tacrolimus orderivatives thereof, has been reported to cause renal dysfunction, such as a reversible decrease in GFR, now recognized as acute CNI nephrotoxicity, as well as irreversible renal function damage as a result of irreversible and progressive tubule-interstitial injury and glomerulosclerosis or chronic CNI nephrotoxicity. In general, a subject presenting with or susceptible to developing acute or chronic drug-induced nephrotoxicity associated with glomerulonephropathy (such as but not limited to autoimmune glomerulonephropathy) or other clinical issues associated with legacy CNIs will benefit from switching to a different CNI, i.e., voclosporin, which is shown herein to exhibit minimal or reduced adverse effects or toxicities, including nephrotoxicity, compared to legacy CNIs.

[0150] In some aspects, legacy CNIs (i.e., traditional CNIs or first-generation CNIs) have been reported to be associated with acute kidney injury, which is hemodynamic and largely reversible after reducing the dose, or as chronic progressive kidney disease, typically irreversible. Other kidney effects of the legacy CNIs include tubular dysfunction and a thrombotic microangiopathy that can lead to acute kidney allograft loss. In some aspects, the legacy CNIs have been reported to show irreversible, histopathologic kidney damage, characterized by arteriolar hyalinosis, interstitial fibrosis, tubulo-interstitial injury, tubular atrophy or glomerular sclerosis.

[0151] In some aspects, the subject selected for treatment with voclosporin has exhibited one or more indicators, such as one or more clinical manifestations, of toxicities or adverse effects from the first CNI. In some aspects, the first CNI is a legacy CNI, such as cyclosporin and tacrolimus.

[0152] In some aspects, legacy CNIs such as cyclosporin or tacrolimus have been shown to contribute to glucose dysregulation, hyperkalemia, hypomagnesemia, drug-drug interactions (DDI) and increase in serum lipids, including inflammatory lipids.

[0153] In some aspects, subjects are selected in accordance with the methods and uses described herein, if the subject has previously received a first CNI for immunosuppression. In some aspects, subjects are selected in accordance with the methods and uses described herein, if the subject has previously received cyclosporin or a derivative thereof for immunosuppression. In some aspects, subjects are selected in accordance with the methods and uses described herein, if the subject has previously received tacrolimus or a derivative thereof for immunosuppression. In some aspects, the provided methods and uses involve selecting a subject that exhibits one or more indicators of adverse effects or toxicitiesassociated with prolonged legacy CNIs, such as drug-induced nephrotoxicity, drug-induced hypercalcemia, drug-induced dyslipidemia, new onset diabetes, or drug-drug interaction with other immunosuppressants. In some aspects, subjects are selected in accordance with the methods and uses described herein, if the subject has previously received a first CNI for immunosuppression and exhibit one or more indicators of adverse events or toxicities, such as drug-induced nephrotoxicity after receiving the first CNI. Exemplary indicators that can be used to assess the presence of adverse effects and toxicities associated with the first CNI include any described herein, for example, in Sections I.B, I.C, and II.C. Methods for Treating or Reducing Adverse Effects or Toxicities

[0154] Provided are methods of treatment that involves administration of voclosporin. In some embodiments, provided are methods for treating or reducing adverse effect or toxicities associated with administration of a legacy CNI, for example with prolonged administration of a legacy CNI. In some aspects, the provided methods and uses involve selecting subjects who have been administered a first CNI, such as cyclosporin, tacrolimus, or a derivative thereof, that may exhibit one or more indicators of adverse effect or toxicities associated with the first CNI. In some aspects, the provided embodiments involve administration of voclosporin to selected subjects. In some aspects, the provided embodiments involve administration of voclosporin, which was observed to be associated with advantages such as reduced or minimal toxicity or adverse effect, to such subjects that exhibit one or more indicators of adverse effect or toxicities associated with the first CNI. In some aspects, the provided methods and uses can treat, prevent or reduce adverse effects or toxicities associated with the legacy CNI administration. In some aspects, the CNI administered to the subject is switched from a legacy CNI to voclosporin. In some aspects, the methods and uses can be employed to treat or reduce adverse effects or toxicities, such as drug-induced nephrotoxicity, drug-induced hypercalcemia, drug-induced dyslipidemia, new onset diabetes, or drug-drug interaction with other immunosuppressants, that can be associated with legacy CNI administration.

[0155] Provided herein is a method of reducing chronic drug-induced nephrotoxicity. In some embodiments, the method of treatment involves selecting a subject who exhibits symptoms of chronic drug-induced nephrotoxicity who has previously received a first CNI, such as cyclosporin, tacrolimus or derivatives thereof, for immunosuppression, for administration of voclosporin. In some embodiments, the selected subject is subsequentlyadministered voclosporin. In some embodiments, the method involves discontinuing the administration of the first CNI. In some embodiments, the method involves administering a therapeutically effective amount of voclosporin to the selected subject who previously received the first CNI for immunosuppression.

[0156] In some aspects, treatment with voclosporin can reduce, prevent, ameliorate or improve drug-induced nephrotoxicity, such as chronic drug-induced nephrotoxicity or acute drug-induced nephrotoxicity. In some aspects, any of the methods, protocols and uses provided herein, can be used for therapeutic purposes to subjects in need of immunosuppression using CNI and may be susceptible to or may exhibit increased risk or susceptibility to drug-induced nephrotoxicity. In some aspects, any of the subjects described herein, for example those who are in need of immunosuppression using CNI and may be susceptible to or may exhibit increased risk or susceptibility to drug-induced nephrotoxicity, may be administered voclosporin according to any of the methods, protocols and uses provided herein. In some aspects, provided are methods of administering voclosporin to a subject who has previously received a first CNI for immunosuppression for at least 30 days, wherein the first CNI is the first CNI, to treat drug-induced nephrotoxicity that can be associated with the first CNI.

[0157] In some aspects, subjects exhibiting one of the following indicators may have or may be at risk of acute drug-induced nephrotoxicity: acute arteriolopathy tubular vacuolization, and thrombotic microangiopathy (TMA). In some aspects, subjects exhibiting one of the following indicators may have or may be at risk of chronic drug-induced nephrotoxicity: interstitial fibrosis and tubular atrophy, medial arteriolar hyalinosis, glomerular capsular fibrosis, global glomerulosclerosis, focal segment glomerulosclerosis (FSGS), juxtaglomerular apparatus hyperplasia, and tubular microcalcifications. In some aspects, the subject is selected for treatment if the subject exhibits one or more of the indicators described herein, associated with drug-induced nephrotoxicity, or other adverse effects or toxicities associated with legacy CNIs.

[0158] In some aspects, subjects who have received or is a candidate for receiving a transplant, such as an organ transplant or a tissue transplant, and a legacy CNI as an immunosuppressant, for example to reduce or prevent transplant rejection, may have or may be at risk of acute drug-induced nephrotoxicity. In some aspects, the subject may have received or is a candidate for receiving a kidney (renal) transplant, a liver transplant, or aheart transplants. In some aspects, the subject may have received or is a candidate for receiving a kidney (renal) transplant.

[0159] Other adverse effects associated with legacy CNIs include dyslipidemia, which can contribute to an increased risk of cardiovascular disease. In some aspects, dyslipidemia can be related to inflammation and the use of immunosuppressants, such as CNI.

[0160] In some aspects, one or more indicators of drug-induced nephrotoxicity include: renal dysfunction, such as altered renal hemodynamics caused, for example, by other therapeutic compounds; osmotic nephrosis caused by common pharmaceutical excipients such as mannitol, glucose, sucrose, dextran, or by radiocontrast agents; recurrent disease (primary HUS / TTP), ischemia-reperfusion injury, renal infection, and side effects of various other drugs, such as mTOR inhibitors and antiviral agents.

[0161] Provided herein is a method of reducing or treating drug-induced hypercalcemia. In some embodiments, the method of treatment involves selecting a subject who exhibits symptoms of a drug-induced hypercalcemia who has previously received the first CNI for immunosuppression, for administration of voclosporin. In some embodiments, the method involves discontinuing the administration of the first CNI. In some embodiments, the method involves administering a therapeutically effective amount of voclosporin to the selected subject who previously received the first CNI for immunosuppression.

[0162] In some aspects, the method involves assessing the fractional calcium excretion in a subject who has previously received previously received the first CNI for immunosuppression. In some aspects, the method involves selecting a subject who exhibits more than 10% increase in factional calcium excretion compared to the fractional calcium excretion of the same subject prior to receiving the first CNI for immunosuppression.

[0163] In some aspects, treatment with voclosporin can reduce, prevent, ameliorate or improve drug-induced hypercalcemia. In some aspects, any of the methods, protocols and uses provided herein, can be used for therapeutic purposes to subjects in need of immunosuppression using CNI and may be susceptible to or may exhibit increased risk or susceptibility to drug-induced hypercalcemia. In some aspects, any of the subjects described herein, for example those who are in need of immunosuppression using CNI and may be susceptible to or may exhibit increased risk or susceptibility to drug-induced hypercalcemia, may be selected to be administered voclosporin according to any of the methods, protocols and uses provided herein.

[0164] Provided herein is a method of reducing or treating new-onset diabetes. In some embodiments, the method of treatment involves selecting a subject who exhibits one or more symptoms of a new-onset diabetes who has previously received the first CNI for immunosuppression, for administration of voclosporin. In some embodiments, the method involves discontinuing the administration of the first CNI. In some embodiments, the method involves administering a therapeutically effective amount of voclosporin to the selected subject who previously received the first CNI for immunosuppression.

[0165] In some aspects, treatment with voclosporin can reduce, prevent, ameliorate or improve new-onset diabetes. In some aspects, any of the methods, protocols and uses provided herein, can be used for therapeutic purposes to subjects in need of immunosuppression using CNI and may be susceptible to or may exhibit increased risk or susceptibility to new-onset diabetes. In some aspects, any of the subjects described herein, for example those who are in need of immunosuppression using CNI and may be susceptible to or may exhibit increased risk or susceptibility to new-onset diabetes, may be selected to be administered voclosporin according to any of the methods, protocols and uses provided herein.

[0166] Provided herein is a method of reducing or treating drug-induced dyslipidemia. In some embodiments, the method of treatment involves selecting a subject who exhibits symptoms of a drug-induced dyslipidemia who has previously received the first CNI for immunosuppression, for administration of voclosporin. In some embodiments, the method involves discontinuing the administration of the first CNI. In some embodiments, the method involves administering a therapeutically effective amount of voclosporin to the selected subject who previously received the first CNI for immunosuppression.

[0167] In some aspects, treatment with voclosporin can reduce, prevent, ameliorate or improve drug-induced dyslipidemia. In some aspects, any of the methods, protocols and uses provided herein, can be used for therapeutic purposes to subjects in need of immunosuppression using CNI and may be susceptible to or may exhibit increased risk or susceptibility to drug-induced dyslipidemia. In some aspects, any of the subjects described herein, for example those who are in need of immunosuppression using CNI and may be susceptible to or may exhibit increased risk or susceptibility to drug-induced dyslipidemia, may be selected to be administered voclosporin according to any of the methods, protocols and uses provided herein.

[0168] Provided herein is a method of reducing or treating drug-induced dyslipidemia. In some embodiments, the method of treatment involves selecting a subject who exhibits symptoms of a drug-induced dyslipidemia who has previously received the first CNI for immunosuppression, for administration of voclosporin. In some embodiments, the method involves discontinuing the administration of the first CNI. In some embodiments, the method involves administering a therapeutically effective amount of voclosporin to the selected subject who previously received the first CNI for immunosuppression.

[0169] In some aspects, treatment with voclosporin can reduce, prevent, ameliorate or improve drug-induced dyslipidemia. In some aspects, any of the methods, protocols and uses provided herein, can be used for therapeutic purposes to subjects in need of immunosuppression using CNI and may be susceptible to or may exhibit increased risk or susceptibility to drug-induced dyslipidemia. In some aspects, any of the subjects described herein, for example those who are in need of immunosuppression using CNI and may be susceptible to or may exhibit increased risk or susceptibility to drug-induced dyslipidemia, may be selected to be administered voclosporin according to any of the methods, protocols and uses provided herein.

[0170] Provided herein is a method of preventing drug-drug interaction with other immunosuppressants, for example, reduction in blood levels of a different immunosuppressant that can be used together with the CNI, or a metabolite thereof. In some aspects, legacy CNIs such as cyclosporin or tacrolimus can be associated with a reduction of blood levels of mycophenolic acid (MPA) when the legacy CNI is used in combination with my cophenolate mofetil (MMF) for immunosuppression. In some embodiments, the method of treatment involves selecting a subject who exhibits symptoms of a drug-drug interaction who has previously received the first CNI for immunosuppression, for administration of voclosporin. In some embodiments, the method involves discontinuing the administration of the first CNI. In some embodiments, the method involves administering a therapeutically effective amount of voclosporin to the selected subject who previously received the first CNI for immunosuppression.

[0171] In some aspects, treatment with voclosporin can reduce, prevent, ameliorate or improve drug-drug interaction, for example preventing a reduction in blood levels of a different immunosuppressant that can be used together with the CNI, such as my cophenolate mofetil (MMF) or a metabolite thereof, mycophenolic acid (MPA). In some aspects, any ofthe methods, protocols and uses provided herein, can be used for therapeutic purposes to subjects in need of immunosuppression using CNI and may be susceptible to or may exhibit increased risk of drug-drug interaction. In some aspects, any of the subjects described herein, for example those who are in need of immunosuppression using CNI and may be susceptible to or may exhibit increased risk of drug-drug interaction, may be selected to be administered voclosporin according to any of the methods, protocols and uses provided herein.

[0172] In some aspects, there are a variety of clinical risk factors for the development of drug-induced nephrotoxicity. Representative diagnosis indicating chronic drug-induced nephrotoxicity susceptibility include: aging, ischemia-reperfusion injury, infection (UTI, CMV), chronic ischemia, diabetes mellitus, hypertension, glomerular ischemia, bone and mineral imbalance, and proteinuria. In some cases, subjects that risk factors for drug-induced nephrotoxicity from previous administration of a first CNI is selected for administration of voclosporin. In some aspects, additional risk factors include systemic overexposure to cyclosporine and tacrolimus, administration of mTOR inhibitors, the presence of a specific ABCB1 genotype of the kidney, expression of the ABCB1 protein in renal tubular epithelial cells, presence of the CYP3A4 / 5 genotype, expression of the CYP3A4 / 5 protein in renal tubular epithelial cells, interaction with other drugs that alter CNI metabolites (e.g., ketoconazole), older kidney age, use of nonsteroidal anti-inflammatory drugs, salt depletion and diuretic use, and genetic polymorphisms of other genes including, but not limited to, transforming growth factor Beta and angiotensin converting enzyme.II. IDENTIFICATION AND SELECTION OF SUBJECTS

[0173] In some aspects, the provided methods and uses involve administration of voclosporin to selected subjects.

[0174] In some aspects, the subject is selected for administration of voclosporin if the subject has previously received a legacy calcineurin inhibitor (CNI) (such as cyclosporin, tacrolimus or derivatives thereof) as a first CNI, for more than a certain period of time, such as more than 30 days.

[0175] In some aspects, the subject is selected for administration of voclosporin if the subject has previously received a legacy CNI (such as cyclosporin, tacrolimus or derivatives thereof), and exhibits one or more indicators of adverse effect or toxicities that can be associated with the first CNI, for example, drug-induced nephrotoxicity, drug-inducedhypercalcemia, drug-induced dyslipidemia, new onset diabetes, or drug-drug interaction with other immunosuppressants.

[0176] In some aspects, the provided methods and uses involve evaluating or assessing one or more indicators of adverse effect or toxicities that can be associated with a legacy CNI. In some aspects, the provided methods and uses involve evaluating or assessing one or more indicators of adverse effect or toxicities that can be associated with cyclosporin. In some aspects, the provided methods and uses involve evaluating or assessing one or more indicators of adverse effect or toxicities that can be associated with tacrolimus. In some aspects, the methods and uses involve evaluating or assessing one or more indicators of adverse effect or toxicities after the subject has started receiving a legacy CNI as a first CNI, and comparing the levels of the same indicators as measured at a baseline, i.e., before receiving the first CNI. In some aspects, a “baseline level” or “baseline measurement,” refers to the levels of the one or more indicators are measured or assessed in the subject before receiving the first CNI, such as cyclosporin, tacrolimus, or derivatives thereof.

[0177] In some aspects, the one or more indicators of adverse effects or toxicities can be evaluated based on methods and assays to assess and monitor such adverse effects and toxicities, such as any described herein. In some aspects, the methods and uses involve evaluating the one or more indicators of adverse effects or toxicities, such as drug-induced nephrotoxicity, and selecting subjects based on particular criteria or thresholds for the particular indicator that is indicative of having or having a risk for the adverse effect or toxicity. In some aspects, the subject is selected based on the criteria or thresholds for the one or more indicators associated with adverse effect or toxicity, and voclosporin is administered to the selected subject. In some aspects, the administration of the first CNI is discontinued before administration of voclosporin begins. In some aspects, in the selected subjects, the CNI used for immunosuppression is switched from a legacy CNI (such as cyclosporin, tacrolimus or derivatives thereof) to voclosporin.

[0178] In some aspects, the provided methods and uses involve assessing the subject’s response to the treatment, or aspects related to the treatment to identify subjects for switching from a legacy calcineurin inhibitor to voclosporin. In some aspects, the methods and uses involve assessing particular aspects of treatment or response, for example, including, but not limited to, assessing or monitoring renal function, renal biopsies, tubular dysfunction, biomarkers, lipid profiles, drug-drug interactions, or glucose dysregulation.A. Prolonged First CNI Administration

[0179] In some aspects, provided are methods for selecting a subject who has previously received a first CNI for immunosuppression for at least 30 days. In some aspects, the first CNI is cyclosporin, tacrolimus, or a derivative thereof. In some embodiments, the subject has previously received a first CNI for at least 30 days, at least 60 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days, at least 1 year, at least 1.5 years, at least 2 years, at least 2.5 years, at least 3 years, or longer. In some aspects, the subject has previously received cyclosporin, tacrolimus, or derivative thereof for at least 2, 3, 4, 5, 6, 9, 12, 18, 24, 30, or 36 months. In some embodiments, the subject is selected for voclosporin administration if the subject has previously received a first CNI for at least 30 days. In some embodiments, the subject is selected for voclosporin administration if the subject has previously received a first CNI for at least 60 days. In some embodiments, the subject is selected for voclosporin administration if the subject has previously received a first CNI for at least 90 days. In some embodiments, the subject is selected for voclosporin administration if the subject has previously received a first CNI for at least 120 days. In some embodiments, the subject is selected for voclosporin administration if the subject has previously received a first CNI for at least 150 days. In some embodiments, the subject is selected for voclosporin administration if the subject has previously received a first CNI for at least 180 days. In some embodiments, the subject is selected for voclosporin administration if the subject has previously received a first CNI for at least 1 year. In some embodiments, the subject is selected for voclosporin administration if the subject has previously received a first CNI for at least 1.5 years. In some embodiments, the subject is selected for voclosporin administration if the subject has previously received a first CNI for at least 2 years. In some embodiments, the subject is selected for voclosporin administration if the subject has previously received a first CNI for at least 2.5 years. In some embodiments, the subject is selected for voclosporin administration if the subject has previously received a first CNI for at least 3 years.B. Renal Function

[0180] In some embodiments, the method or the use further comprises or involves assessing the renal function of the subject, for example, for KTR subjects or subjects involved in immunosuppression due to conditions of the kidney (such as lupus nephritis (LN), to identifying subjects for switching from a legacy CNI to voclosporin. In someaspects, the one or more indicators of drug-induced nephrotoxicity is assessed based on the one or more renal biopsies.

[0181] In some embodiments, the subject is selected if the subject has increased susceptibility to chronic drug-induced nephrotoxicity after receiving the first CNI, as assessed by evaluating renal function. In some embodiments, the subject is selected if the subject has increased susceptibility to drug-induced nephrotoxicity compared to a corresponding population of individuals. In some embodiments, the population of individuals refers to a diseased general population. In some embodiments, the population of individuals refers to general population of a specific gender. In some embodiments, the population of individuals refers to general population of a specific race. In some embodiments, the population of individuals refers to general population of a specific age group. In some embodiments, the population of individuals refers to general population of a specific geographical region. In some aspects, the provided embodiments include assessing or monitoring the risk of drug- induced nephrotoxicity, for example, by assessing or measuring one or more of the indicators described herein, or changes of the one or more of the indicators described herein.

[0182] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises renal impairment, or any assessments or indicators associated with or indicative of renal impairment. In some embodiments, the subject is selected if the subject exhibits renal impairment after receiving the first CNI. In some aspects, subject with renal impairment is determined based on creatinine clearance as calculated by the Cockcroft-Gault formula of 60 to < 90 mL / min (mild impairment), 30 to < 60 mL / min (moderate impairment), or 15 to < 30 mL / min (severe impairment), or a matched control subject (by age and body mass index). In some embodiments, the subject is selected if the subject exhibits severe renal impairment (CLcr of 30 mL / min or lower) after receiving the first CNI. In some embodiments, the subject exhibits severe renal impairment at a baseline eGFR, wherein the baseline eGFR is any one of about > 30, > 35, > 40, > 45, > 50, > 60 or > 70 ml / min / 1.73 m2In some embodiments, the voclosporin Cmaxand / or AUC are increased in subjects with severe renal impairment compared to corresponding subjects without such impairments. In some embodiments, the voclosporin Cmax is increased by about any one of 1.1 -fold, 1.2-fold, 1.3- fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2.0-fold, 3.0-fold, 5.0-fold, 10.0- fold or more in subjects with severe renal impairment compared to corresponding subjects without such impairments. In some embodiments, the voclosporin AUC is increased by aboutany one of 1.1-fold, 1.2-fold, 1.3-fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2.0-fold, 3.0-fold, 5.0-fold, 10.0-fold or more in subjects with severe renal impairment compared to corresponding subjects without such impairments.

[0183] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises symptoms of renal disease, or any assessments or indicators associated with or indicative of symptoms of renal disease. In some embodiments, the subject is selected if the subject exhibits one or more symptoms of renal diseases after receiving the first CNI. In some embodiments, the subject suffers from one or more renal diseases, wherein the one or more renal diseases contribute to increased susceptibility to chronic drug-induced nephrotoxicity. In some embodiments, the subject is selected if the subject has increased susceptibility to drug-induced nephrotoxicity, the subject exhibits one or more forms of glomerulonephropathy. In some embodiments, the subject is selected if the subject has increased susceptibility to drug-induced nephrotoxicity, and wherein the subject exhibits one or more forms of glomerulonephropathy, prolonged administration of legacy CNIs (such as cyclosporin or tacrolimus) can result in long term renal damage, such as but not limited to additional acute and chronic nephrotoxicity.

[0184] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises glomerulonephropathy, or any assessments or indicators associated with or indicative of glomerulonephropathy. In some embodiments, the subject exhibits glomerulonephropathy. In some embodiments, the subject exhibits chronic glomerulonephropathy. In some embodiments, the subject exhibits inflammatory glomerulonephropathy. In some embodiments, the subject exhibits non-inflammatory glomerulonephropathy. In some embodiments, the subject exhibits autoimmune glomerulonephropathy. In some embodiments, the subject exhibits acute glomerulonephropathy. In some embodiments, the subject exhibits glomerulonephritis. In some embodiments, the subject exhibits chronic glomerulonephritis. In some embodiments, the subject exhibits acute glomerulonephritis.

[0185] In some embodiments, the subject exhibits an inflammatory renal disease. In some embodiments, the subject exhibits anon-inflammatory renal disease. In some embodiments, the subject exhibits an inflammatory renal disease in the context of autoimmunity. In some embodiments, the autoimmune renal disease may result from a selfantigen within renal tissue (such as Goodpasture antigen). In some embodiments, theautoimmune renal disease may result from self-antigens residing outside the kidney that causes immune-complexes within the kidneys, triggering tissue damage events (e.g., lupus nephritis). In some embodiments, the autoimmune renal disease may result from antigens and / or antibodies that are neither derived nor deposited within the kidneys, but wherein interaction of antibodies with antigens or with antigen-bearing cells cause the disease (e.g., autoantibodies to neutrophil cytoplasmic antigens (ANCA)-associated vasculitis or glomerulonephritis). In some embodiments, the subject suffers from anti -glomerular base membrane disease (anti-GBM disease). In some embodiments, the subject suffers from lupus nephritis. In some embodiments, the subject suffers from systemic lupus erythematosus (SLE). In some aspects, up to half of subjects with systemic lupus erythematosus (SLE) can develop LN, which can result in severe and permanent damage to the kidneys and, in some cases, renal failure. In some embodiments, the subject suffers from ANCA-associated vasculitis. In some embodiments, the subject suffers from ANCA-associated glomerulonephritis.C. Tubular Dysfunction

[0186] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises tubular dysfunction, or any assessments or indicators associated with or indicative of tubular dysfunction. In some embodiments, the subject is selected based on assessment of drug-induced tubular dysfunction and / or ion homeostasis after receiving the first CNI. In some embodiments, the method includes selecting subjects based on assessing the level of one or more urinary electrolytes of the subject compared to a baseline level as assessed prior to receiving the first CNI such as cyclosporin, tacrolimus, or derivatives thereof, and if the level of the one or more urinary electrolyte is decreased or increased by more than a predetermined value, compared to baseline levels, selecting the subject for voclosporin administration. In some of any embodiments, the urinary electrolyte is selected from one or more of magnesium, sodium and potassium.

[0187] In some of any embodiments, the urinary electrolyte is magnesium, and the predetermined value range is about 1 mg / dL to 40 mg / dL. In some of any embodiments, the urinary electrolyte is magnesium, and the predetermined value is about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, or 40 mg / dL. In some of any embodiments, the urinary electrolyte is magnesium, and the predetermined value range is about 10 mg / dL to 30 mg / dL. In some of any embodiments, the urinary electrolyte ismagnesium, and the predetermined value is about 20 mg / dL. In some of any embodiments, the urinary electrolyte is sodium, and the predetermined value range is about 5 mmol / L to 100 mmol / L. In some of any embodiments, the urinary electrolyte is sodium, and the predetermined value is about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90 or 100 mmol / L. In some of any embodiments, the urinary electrolyte is sodium, and the predetermined value range is about 30 mmol / L to 70 mmol / L. In some of any embodiments, the urinary electrolyte is sodium, and the predetermined value is about 50 mmol / L. In some of any embodiments, the urinary electrolyte is potassium, and the predetermined value range is about 1 mmol / L to 25 mmol / L. In some of any embodiments, the urinary electrolyte is potassium, and the predetermined value is about 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24 or 25 mmol / L. In some of any embodiments, the urinary electrolyte is potassium, and the predetermined value range is about 5 mmol / L to 15 mmol / L. In some of any embodiments, the urinary electrolyte is potassium, and the predetermined value is about 10 mmol / L.

[0188] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises drug-induced hyperkalemia, hypomagnesemia, magnesium wasting or hyperuricemia, or any assessments or indicators associated with or indicative of drug-induced hyperkalemia, hypomagnesemia, magnesium wasting or hyperuricemia. In some embodiments, the subject is assessed for and selected based on the presence of drug-induced hyperkalemia, hypomagnesemia, magnesium wasting or hyperuricemia after receiving the first CNI. Hyperkalemia is evaluated from collected serum samples and classified into mild (5.1- < 6 mmol / 1), moderate (6- < 7 mmol / 1) and severe (> 7 mmol / 1). Low serum magnesium (hypomagnesemia) is determined as serum magnesium levels below the standard reference range, or less than 1.4-1.8 mg / dL. Urine analysis exhibiting magnesium excretion of more than 2 mEq (1 mmol or 24mg) is classified as indicative of renal magnesium wasting. Elevated uric acid (hyperuricemia) is evaluated from collected serum samples, and are classified as values above the standard upper limit of 6.0-7.0 mg / dL.

[0189] In some embodiments, the methods and uses involve assessing hyperkalemia, hypomagnesemia, magnesium wasting and hyperuricemia in serum and urine samples of the subject compared to a baseline level, and if hyperkalemia, hypomagnesemia, magnesium wasting and hyperuricemia is detected, selecting the subject for voclosporin administration.

[0190] In some embodiments, hyperkalemia is determined by a serum potassium level ofmore than about any one of 4, 5, 6, 7, 8, 9, or 10 mmol / L. In some embodiments, hyperkalemia is determined by a serum potassium level of more than about 4 mmol / L. In some embodiments, hyperkalemia is determined by a serum potassium level of more than about 5 mmol / L. In some embodiments, hyperkalemia is determined by a serum potassium level of more than about 6 mmol / L. In some aspects, hypomagnesemia is determined by a serum magnesium level less than about any one of 0.9, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1, 2.2, 2.3, 2.4 or 2.5 mg / dL. In some aspects, hypomagnesemia is determined by a serum magnesium level less than about 1.2 mg / dL. In some aspects, hypomagnesemia is determined by a serum magnesium level less than about 1.4 mg / dL. In some aspects, hypomagnesemia is determined by a serum magnesium level less than about 1.6 mg / dL. In some aspects, magnesium wasting is determined by a urine magnesium level of more than about any one of 0.8, 1.0, 1.2, 1.4, 1.6, 1.8, 2, 2.2, 2.4, 2.6, 2.8, 3.0, 3.5 or 4.0 mEq. In some aspects, magnesium wasting is determined by a urine magnesium level of more than about 1.0 mEq. In some aspects, magnesium wasting is determined by a urine magnesium level of more than about 2.0 mEq. In some aspects, magnesium wasting is determined by a urine magnesium level of more than about 3.0 mEq. In some aspects, hyperuricemia is determined by a serum uric acid level of more than about any one of 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5 or 10.0 mg / dL. In some aspects, hyperuricemia is determined by a serum uric acid level of more than about 5.0 mg / dL. In some aspects, hyperuricemia is determined by a serum uric acid level of more than about 7.0 mg / dL. In some aspects, hyperuricemia is determined by a serum uric acid level of more than about 9.0 mg / dL.

[0191] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises hypercalcemia, or any assessments or indicators associated with or indicative of hypercalcemia. In some embodiments, the methods and uses involve assessing hypercalcemia in serum samples of the subject compared to a baseline level as assessed prior to receiving the first CNI such as cyclosporin, tacrolimus, or derivatives thereof, and if hypercalcemia is detected, selecting the subject for voclosporin administration.

[0192] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises increase in fractional calcium excretion, or any assessments or indicators associated with or indicative of increase in fractional calcium excretion. In some embodiments, the subject selected for administration of voclosporin exhibits a 1% or greater, 5% or greater, 10% or greater, 15% or greater, or 20% or greater increase in fractionalcalcium excretion as assessed after receiving the first CNI, compared to a baseline fractional calcium excretion as assessed prior to receiving the first CNI. In some embodiments, the subject selected for administration of voclosporin exhibits a 10% or greater increase in fractional calcium excretion as assessed after receiving the first CNI, compared to a baseline fractional calcium excretion.

[0193] In some embodiments, the selected subject exhibits 5% or greater, 7.5% or greater, 10% or greater, 12.5 % or greater, 15% of greater increase in fractional calcium excretion as assessed after receiving a first CNI for immunosuppression compared to a baseline fractional calcium excretion assessed prior to receiving the first CNI. In some embodiments, the subject is selected for treatment if the subject exhibits a 10% or greater increase in fractional calcium excretion after receiving the first CNI. In some embodiments, the subject is selected for treatment if the subject exhibits a 20% or greater increase in fractional calcium excretion after receiving the first CNI. In some embodiments, the subject is selected for treatment if the subject exhibits a 30% or greater increase in fractional calcium excretion after receiving the first CNI. In some embodiments, the subject is selected for treatment if the subject exhibits a 40% or greater increase in fractional calcium excretion after receiving the first CNI. In some embodiments, the subject is selected for treatment if the subject exhibits a 50% or greater increase in fractional calcium excretion after receiving the first CNI. In some embodiments, the subject is selected for treatment if the subject exhibits a 60% or greater increase in fractional calcium excretion after receiving the first CNI.

[0194] In some embodiments, the selected subject exhibits 10% or greater increase in fractional calcium excretion as assessed after receiving a first CNI for immunosuppression compared to a baseline fractional calcium excretion assessed prior to receiving the first CNI. In some embodiments, the selected subject exhibits 20% or greater increase in fractional calcium excretion as assessed after receiving a first CNI for immunosuppression compared to a baseline fractional calcium excretion assessed prior to receiving the first CNI. In some embodiments, the selected subject exhibits 30% or greater increase in fractional calcium excretion as assessed after receiving a first CNI for immunosuppression compared to a baseline fractional calcium excretion assessed prior to receiving the first CNI. In some embodiments, the selected subject exhibits 40% or greater increase in fractional calcium excretion as assessed after receiving a first CNI for immunosuppression compared to a baseline fractional calcium excretion assessed prior to receiving the first CNI. In someembodiments, the selected subject exhibits 50% or greater increase in fractional calcium excretion as assessed after receiving a first CNI for immunosuppression compared to a baseline fractional calcium excretion assessed prior to receiving the first CNI. In some embodiments, the selected subject exhibits 60% or greater increase in fractional calcium excretion as assessed after receiving a first CNI for immunosuppression compared to a baseline fractional calcium excretion assessed prior to receiving the first CNI.

[0195] In some embodiments, the subject is selected if the subject exhibits increased fractional calcium excretion. In some embodiments, the fractional calcium excretion is evaluated at a baseline. In some aspects, the baseline is prior to the subject receiving the first CNI, such as cyclosporin, tacrolimus, or a derivative thereof. In some aspects, fractional calcium excretion is evaluated after the subject has received the first CNI, such as cyclosporin, tacrolimus, or a derivative thereof. In some embodiments, the subject is selected for if the fractional calcium excretion is increased compared to the baseline level by about 10%, 12.5%, 15%, 17.5%, or 20% or more. In some embodiments, the subject is selected for if the fractional calcium excretion is increased compared to the baseline level by about 10% or more. In some embodiments, the subject is selected for if the fractional calcium excretion is increased compared to the baseline level by about 12.5% or more. In some embodiments, the subject is selected for if the fractional calcium excretion is increased compared to the baseline level by about 15% or more. In some embodiments, the subject is selected for if the fractional calcium excretion is increased compared to the baseline level by about 17.5% or more. In some embodiments, the subject is selected for if the fractional calcium excretion is increased compared to the baseline level by about 20% or more.

[0196] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises increase in fractional calcium excretion, or any assessments or indicators associated with or indicative of increase in fractional calcium excretion. In some embodiments, the subject selected for administration of voclosporin exhibits a 2-fold or greater, 3-fold or greater, 4-fold or greater, or 5-fold or greater increase in fractional calcium excretion as assessed after receiving the first CNI, compared to a baseline fractional calcium excretion as assessed prior to receiving the first CNI. In some embodiments, the subject selected for administration of voclosporin exhibits a 2-fold or greater in fractional calcium excretion as assessed after receiving the first CNI, compared to a baseline fractional calcium excretion. In some embodiments, the subject selected for administration of voclosporinexhibits a 3-fold or greater in fractional calcium excretion as assessed after receiving the first CNI, compared to a baseline fractional calcium excretion. In some embodiments, the subject selected for administration of voclosporin exhibits a 4-fold or greater in fractional calcium excretion as assessed after receiving the first CNI, compared to a baseline fractional calcium excretion. In some embodiments, the subject selected for administration of voclosporin exhibits a 5-fold or greater in fractional calcium excretion as assessed after receiving the first CNI, compared to a baseline fractional calcium excretion.

[0197] In some embodiments, the selected subject exhibits a 2-fold or greater, 3 -fold or greater, 4-fold or greater, or 5-fold or greater increase in fractional calcium excretion as assessed after receiving a first CNI for immunosuppression compared to a baseline fractional calcium excretion assessed prior to receiving the first CNI. In some embodiments, the subject is selected for treatment if the subject exhibits a 2-fold or greater increase in fractional calcium excretion after receiving the first CNI. In some embodiments, the subject is selected for treatment if the subject exhibits a 3-fold or greater increase in fractional calcium excretion after receiving the first CNI. In some embodiments, the subject is selected for treatment if the subject exhibits a 4-fold or greater increase in fractional calcium excretion after receiving the first CNI. In some embodiments, the subject is selected for treatment if the subject exhibits a 5-fold or greater increase in fractional calcium excretion after receiving the first CNI. In some embodiments, the subject is selected if the subject exhibits increased fractional calcium excretion. In some embodiments, the fractional calcium excretion is evaluated at a baseline. In some aspects, the baseline is prior to the subject receiving the first CNI, such as cyclosporin, tacrolimus, or a derivative thereof. In some aspects, fractional calcium excretion is evaluated after the subject has received the first CNI, such as cyclosporin, tacrolimus, or a derivative thereof.

[0198] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 1% or greater, 5% or greater, 10% or greater, 15% or greater, 20% or greater, 25% or greater, 30% or greater, 35% or greater, 40% or greater, 45% or greater, or 50% or greater decrease in fractional calcium excretion, as assessed after receiving the voclosporin, compared to the fractional calcium excretion as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 10% or greater decrease in fractional calcium excretion, as assessed after receiving the voclosporin,compared to the fractional calcium excretion as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 25% or greater decrease in fractional calcium excretion, as assessed after receiving the voclosporin, compared to the fractional calcium excretion as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 45% or greater decrease in fractional calcium excretion, as assessed after receiving the voclosporin, compared to the fractional calcium excretion as assessed after receiving the first CNI, but before receiving voclosporin.

[0199] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 2-fold or greater, 3-fold or greater, 4-fold or greater, or 5-fold or greater decrease in fractional calcium excretion, as assessed after receiving the voclosporin, compared to the fractional calcium excretion as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 2-fold or greater decrease in fractional calcium excretion, as assessed after receiving the voclosporin, compared to the fractional calcium excretion as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 3 -fold or greater decrease in fractional calcium excretion, as assessed after receiving the voclosporin, compared to the fractional calcium excretion as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 4-fold or greater decrease in fractional calcium excretion, as assessed after receiving the voclosporin, compared to the fractional calcium excretion as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 5-fold or greater decrease in fractional calcium excretion, as assessed after receiving the voclosporin, compared to the fractional calcium excretion as assessed after receiving the first CNI, but before receiving voclosporin.

[0200] In some aspects, the provided embodiments include assessing or monitoring the risk of drug-induced hypercalcemia, for example, by assessing or measuring one or more of the indicators described herein, or changes of the one or more of the indicators. In someaspects, the subject is selected for administration of voclosporin if the subject exhibits one or more indicators associated with drug-induced hypercalcemia after administration of the first CNI.

[0201] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises hypercalciuria, or any assessments or indicators associated with or indicative of hypercal ciuria. In some embodiments, the subject selected for administration of voclosporin exhibits hypercalciuria after receiving the first CNI. In some embodiments, the subject selected for administration of voclosporin exhibits a 10% or greater, 15% or greater, 20% or greater, 30% or greater, 40% or greater or 50% or greater increase in urine calcium levels as assessed after receiving the first CNI, compared to a baseline urine calcium level. In some embodiments, the subject selected for administration of voclosporin exhibits a 10% or greater increase in urine calcium levels as assessed after receiving the first CNI, compared to a baseline urine calcium level. In some embodiments, the subject selected for administration of voclosporin exhibits a 15% or greater increase in urine calcium levels as assessed after receiving the first CNI, compared to a baseline urine calcium level. In some embodiments, the subject selected for administration of voclosporin exhibits a 20% or greater increase in urine calcium levels as assessed after receiving the first CNI, compared to a baseline urine calcium level. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater increase in urine calcium levels as assessed after receiving the first CNI, compared to a baseline urine calcium level. In some embodiments, the subject selected for administration of voclosporin exhibits a 40% or greater increase in urine calcium levels as assessed after receiving the first CNI, compared to a baseline urine calcium level. In some embodiments, the subject selected for administration of voclosporin exhibits a 50% or greater increase in urine calcium levels as assessed after receiving the first CNI, compared to a baseline urine calcium level.

[0202] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 10% or greater, 15% or greater, 20% or greater, 30% or greater, 40% or greater or 50% or greater decrease in urine calcium levels, as assessed after receiving the voclosporin, compared to the urine calcium level as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 10% or greater decrease in urine calcium levels, as assessed after receiving the voclosporin, compared to theurine calcium level as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15% or greater decrease in urine calcium levels, as assessed after receiving the voclosporin, compared to the urine calcium level as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 20% or greater decrease in urine calcium levels, as assessed after receiving the voclosporin, compared to the urine calcium level as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30% or greater decrease in urine calcium levels, as assessed after receiving the voclosporin, compared to the urine calcium level as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 40% or greater decrease in urine calcium levels, as assessed after receiving the voclosporin, compared to the urine calcium level as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 50% or greater decrease in urine calcium levels, as assessed after receiving the voclosporin, compared to the urine calcium level as assessed after receiving the first CNI, but before receiving voclosporin.

[0203] In some embodiments, the subject is selected if the subject has increased susceptibility to drug-induced hypercalcemia after receiving the first CNI. In some embodiments, the subject is selected if the subject has increased susceptibility to drug- induced hypercalcemia compared to a corresponding population of individuals. In some embodiments, the population of individuals refers to a diseased general population. In some embodiments, the population of individuals refers to general population of a specific gender. In some embodiments, the population of individuals refers to general population of a specific race. In some embodiments, the population of individuals refers to general population of a specific age group. In some embodiments, the population of individuals refers to general population of a specific geographical region.

[0204] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises increase in fractional magnesium excretion, or any assessments or indicators associated with or indicative of increase in fractional magnesium excretion. In someembodiments, the subject selected for administration of voclosporin exhibits a 1.2-fold or greater, 1.3-fold or greater, 1.4-fold or greater, 1.5-fold or greater, 1.6-fold or greater, 1.7- fold or greater, 1.8-fold or greater, 1.9-fold or greater, or 2.0-fold or greater increase in fractional magnesium excretion as assessed after receiving the first CNI, compared to a baseline fractional magnesium excretion as assessed prior to receiving the first CNI. In some embodiments, the subject selected for administration of voclosporin exhibits a 1.2-fold or greater in fractional magnesium excretion as assessed after receiving the first CNI, compared to a baseline fractional magnesium excretion. In some embodiments, the subject selected for administration of voclosporin exhibits a 1.3-fold or greater in fractional magnesium excretion as assessed after receiving the first CNI, compared to a baseline fractional magnesium excretion. In some embodiments, the subject selected for administration of voclosporin exhibits a 1.4-fold or greater in fractional magnesium excretion as assessed after receiving the first CNI, compared to a baseline fractional magnesium excretion. In some embodiments, the subject selected for administration of voclosporin exhibits a 1.5-fold or greater in fractional magnesium excretion as assessed after receiving the first CNI, compared to a baseline fractional magnesium excretion.

[0205] In some embodiments, the selected subject exhibits a 1.2-fold or greater, 1.3-fold or greater, 1.4-fold or greater, or 1.5-fold or greater increase in fractional magnesium excretion as assessed after receiving a first CNI for immunosuppression compared to a baseline fractional magnesium excretion assessed prior to receiving the first CNI. In some embodiments, the subject is selected for treatment if the subject exhibits a 1.2-fold or greater increase in fractional magnesium excretion after receiving the first CNI. In some embodiments, the subject is selected for treatment if the subject exhibits a 1.3 -fold or greater increase in fractional magnesium excretion after receiving the first CNI. In some embodiments, the subject is selected for treatment if the subject exhibits a 1.4-fold or greater increase in fractional magnesium excretion after receiving the first CNI. In some embodiments, the subject is selected for treatment if the subject exhibits a 1.5 -fold or greater increase in fractional magnesium excretion after receiving the first CNI. In some embodiments, the subject is selected if the subject exhibits increased fractional magnesium excretion. In some embodiments, the fractional magnesium excretion is evaluated at a baseline. In some aspects, the baseline is prior to the subject receiving the first CNI, such as cyclosporin, tacrolimus, or a derivative thereof. In some aspects, fractional magnesium excretion is evaluated after the subject has received the first CNI, such as cyclosporin,tacrolimus, or a derivative thereof.

[0206] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 1.2-fold or greater, 1.3-fold or greater, 1.4-fold or greater, 1.5-fold or greater, 1.6-fold or greater, 1.7-fold or greater, 1.8-fold or greater, 1.9- fold or greater, or 2.0-fold or greater decrease in fractional magnesium excretion, as assessed after receiving the voclosporin, compared to the fractional magnesium excretion as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 1.2-fold or greater decrease in fractional magnesium excretion, as assessed after receiving the voclosporin, compared to the fractional magnesium excretion as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 1.4-fold or greater decrease in fractional magnesium excretion, as assessed after receiving the voclosporin, compared to the fractional magnesium excretion as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 1.6-fold or greater decrease in fractional magnesium excretion, as assessed after receiving the voclosporin, compared to the fractional magnesium excretion as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 1.8-fold or greater decrease in fractional magnesium excretion, as assessed after receiving the voclosporin, compared to the fractional magnesium excretion as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 2.0-fold or greater decrease in fractional magnesium excretion, as assessed after receiving the voclosporin, compared to the fractional magnesium excretion as assessed after receiving the first CNI, but before receiving voclosporin.

[0207] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises increase in levels of calbindin-D28K, or any assessments or indicators associated with or indicative of increase in levels of calbindin-D28K. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a change in calbindin-D28K levels, which is associated with drug-induced hypercalcemia and tubular dysfunction. Insome aspects, the subject is selected for treatment if the subject exhibits a 2-fold or greater, 3- fold or greater, 4-fold or greater, 5 -fold or greater, 6-fold or greater, 7-fold or greater, 8-fold or greater, 9-fold or greater, or 10-fold or greater increase in the level of calbindin-D28K after receiving the first CNI. In some aspects, the subject is selected for treatment if the subject exhibits a 2-fold or greater increase in the level of calbindin-D28K after receiving the first CNI. In some aspects, the subject is selected for treatment if the subject exhibits a 3-fold or greater increase in the level of calbindin-D28K after receiving the first CNI. In some aspects, the subject is selected for treatment if the subject exhibits a 4-fold or greater increase in the level of calbindin-D28K after receiving the first CNI. In some aspects, the subject is selected for treatment if the subject exhibits a 5-fold or greater increase in the level of calbindin-D28K after receiving the first CNI. In some aspects, the subject is selected for treatment if the subject exhibits a 6-fold or greater increase in the level of calbindin-D28K after receiving the first CNI. In some aspects, the subject is selected for treatment if the subject exhibits a 7-fold or greater increase in the level of calbindin-D28K after receiving the first CNI. In some aspects, the subject is selected for treatment if the subject exhibits an 8- fold or greater increase in the level of calbindin-D28K after receiving the first CNI. In some aspects, the subject is selected for treatment if the subject exhibits a 9-fold or greater increase in the level of calbindin-D28K after receiving the first CNI. In some aspects, the subject is selected for treatment if the subject exhibits a 10-fold or greater increase in the level of calbindin-D28K after receiving the first CNI.

[0208] In some embodiments, the subject selected for administration of voclosporin exhibits a 1-fold or greater, 1.5-fold or greater, 2-fold or greater, 2.5-fold or greater or 3-fold or greater decrease in the level of calbindin-D28K as assessed after receiving the first CNI, compared to a baseline fractional calcium excretion. In some embodiments, the subject selected for administration of voclosporin exhibits a 1.5-fold or greater decrease in the level of calbindin-D28K as assessed after receiving the first CNI, compared to a baseline fractional calcium excretion. In some embodiments, the subject selected for administration of voclosporin exhibits a 2-fold or greater decrease in the level of calbindin-D28K as assessed after receiving the first CNI, compared to a baseline fractional calcium excretion. In some embodiments, the subject selected for administration of voclosporin exhibits a 2.5-fold or greater decrease in the level of calbindin-D28K as assessed after receiving the first CNI, compared to a baseline fractional calcium excretion.

[0209] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 2-fold or greater, 3-fold or greater, 4-fold or greater, 5- fold or greater, 6-fold or greater, 7-fold or greater, 8-fold or greater, 9-fold or greater, or 10- fold or greater decrease in level of calbindin-D28K, as assessed after receiving the voclosporin, compared to the level of calbindin-D28K as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 2-fold or greater decrease in level of calbindin-D28K, as assessed after receiving the voclosporin, compared to the level of calbindin-D28K as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 4-fold or greater decrease in level of calbindin- D28K, as assessed after receiving the voclosporin, compared to the level of calbindin-D28K as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 6-fold or greater decrease in level of calbindin-D28K, as assessed after receiving the voclosporin, compared to the level of calbindin-D28K as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits an 8-fold or greater decrease in level of calbindin-D28K, as assessed after receiving the voclosporin, compared to the level of calbindin-D28K as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 10-fold or greater decrease in level of calbindin-D28K, as assessed after receiving the voclosporin, compared to the level of calbindin-D28K as assessed after receiving the first CNI, but before receiving voclosporin.

[0210] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises increase in sodium-chloride cotransporter (NCC) levels, or any assessments or indicators associated with or indicative of increase in sodium-chloride cotransporter (NCC) levels. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a change in sodium-chloride cotransporter (NCC) levels, which is associated with drug-induced hypercalcemia and tubular dysfunction. In some aspects, the subject is selected for treatment if the subject exhibits a 2-fold, 3-fold, 4-fold, or 5-fold or greater decrease in the level of NCC after receiving the first CNI. In some embodiments, the subject selected for administration of voclosporin exhibits a 1-fold or greater, 1.5-fold or greater, 2-fold orgreater, 2.5-fold or greater or 3-fold or greater decrease in the level of sodium-chloride cotransporter (NCC) as assessed after receiving the first CNI, compared to a baseline fractional calcium excretion. In some embodiments, the subject is selected for treatment if the subject exhibits a 1.5-fold or greater increase in the level of NCC after receiving the first CNI. In some embodiments, the subject is selected for treatment if the subject exhibits a 2- fold or greater decrease in the level of NCC after receiving the first CNI. In some embodiments, the subject is selected for treatment if the subject exhibits a 3 -fold or greater decrease in the level of NCC after receiving the first CNI. In some embodiments, the subject is selected for treatment if the subject exhibits a 4-fold or greater decrease in the level of NCC after receiving the first CNI. In some embodiments, the subject is selected for treatment if the subject exhibits a 5-fold or greater decrease in the level of NCC after receiving the first CNI. In some embodiments, the subject selected for administration of voclosporin exhibits a 1.5-fold or greater decrease in the level of sodium-chloride cotransporter (NCC) as assessed after receiving the first CNI, compared to a baseline level of sodium-chloride cotransporter (NCC). In some embodiments, the subject selected for administration of voclosporin exhibits a 2-fold or greater decrease in the level of sodiumchloride cotransporter (NCC) as assessed after receiving the first CNI, compared to a baseline level of sodium-chloride cotransporter (NCC). In some embodiments, the subject selected for administration of voclosporin exhibits a 3-fold or greater decrease in the level of sodiumchloride cotransporter (NCC) as assessed after receiving the first CNI, compared to a baseline level of sodium-chloride cotransporter (NCC). In some embodiments, the subject selected for administration of voclosporin exhibits a 4-fold or greater decrease in the level of sodiumchloride cotransporter (NCC) as assessed after receiving the first CNI, compared to a baseline level of sodium-chloride cotransporter (NCC). In some embodiments, the subject selected for administration of voclosporin exhibits a 5-fold or greater decrease in the level of sodiumchloride cotransporter (NCC) as assessed after receiving the first CNI, compared to a baseline level of sodium-chloride cotransporter (NCC).

[0211] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 1-fold or greater, 1.5-fold or greater, 2-fold or greater, 2.5-fold or greater, 3-fold or greater, 4-fold or greater, or 5-fold or greater increase in the level of sodium-chloride cotransporter (NCC) as assessed after receiving the voclosporin, compared to the level of sodium-chloride cotransporter (NCC) as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected foradministration of voclosporin, after receiving the voclosporin, exhibits 2-fold or greater increase in the level of sodium-chloride cotransporter (NCC) as assessed after receiving the voclosporin, compared to the level of sodium-chloride cotransporter (NCC) as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits 3-fold or greater increase in the level of sodium-chloride cotransporter (NCC) as assessed after receiving the voclosporin, compared to the level of sodium-chloride cotransporter (NCC) as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits 4-fold or greater increase in the level of sodium-chloride cotransporter (NCC) as assessed after receiving the voclosporin, compared to the level of sodium-chloride cotransporter (NCC) as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits 5-fold or greater increase in the level of sodiumchloride cotransporter (NCC) as assessed after receiving the voclosporin, compared to the level of sodium-chloride cotransporter (NCC) as assessed after receiving the first CNI, but before receiving voclosporin.

[0212] In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater decrease in the expression level of one or more genes selected from the group consisting of Slcl2a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8al, and Calbl, as assessed after receiving the first CNI, compared to a respective baseline expression level of the one or more genes as assessed prior to receiving the first CNI. In some embodiments, the subject is selected if the subject exhibits a decrease in the expression level of one or more genes selected from the group consisting of Slcl2a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8al, and Calbl. In some embodiments, the expression level of the one or more genes is evaluated at a baseline. In some aspects, the baseline is prior to the subject receiving the first CNI, such as cyclosporin, tacrolimus, or a derivative thereof. In some aspects, the expression level of the one or more genes is evaluated after the subject has received the first CNI, such as cyclosporin, tacrolimus, or a derivative thereof.

[0213] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30% or greater increase in the expression level of one or more genes selected from the group consisting of Slcl2a3, Trpm6, Cnnm2, Egf, Trpv5,Slc8al, and Calbl, as assessed after receiving the voclosporin, compared to the expression level of one or more genes selected from the group consisting of Slcl2a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8al, and Calbl, as assessed after receiving the first CNI, but before receiving voclosporin.

[0214] In some embodiments, the subject selected for administration of voclosporin exhibits a 30%, 40%, 50%, 60%, or 70% or greater decrease in the expression level of the solute carrier family 12 member A3 (Slcl2a3) gene, as assessed after receiving the first CNI, compared to a baseline expression level of Slcl2a3as assessed prior to receiving the first CNI. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% greater decrease in the expression level of the solute carrier family 12 member A3 (Slcl2a3) gene, as assessed after receiving the first CNI, compared to a baseline expression level of Slcl2a3as assessed prior to receiving the first CNI. In some embodiments, the subject selected for administration of voclosporin exhibits a 30%, 40%, 50%, 60%, or 70% or greater decrease in the expression level of Slcl2a3 compared to baseline. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater decrease in the expression level of Slcl2a3 compared to baseline.

[0215] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30%, 40%, 50%, 60%, or 70% or greater increase in the expression level of the solute carrier family 12 member A3 (Slcl2a3) gene, as assessed after receiving the voclosporin, compared to the expression level of the solute carrier family 12 member A3 (Slcl2a3) gene, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30% or greater increase in the expression level of the solute carrier family 12 member A3 (Slcl2a3) gene, as assessed after receiving the voclosporin, compared to the expression level of the solute carrier family 12 member A3 (Slcl2a3) gene, as assessed after receiving the first CNI, but before receiving voclosporin.

[0216] In some embodiments, the subject selected for administration of voclosporin exhibits a 30%, 40%, 50%, 60%, or 70% or greater decrease in the expression level of the transient receptor potential cation channel subfamily M Member 6 (Trpm6) gene, as assessed after receiving the first CNI, compared to a baseline expression level of Trpm6as assessed prior to receiving the first CNI. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater decrease in the expression level of the transientreceptor potential cation channel subfamily M Member 6 (Trpm6) gene, as assessed after receiving the first CNI, compared to a baseline expression level of Trpm6as assessed prior to receiving the first CNI. In some embodiments, the subject selected for administration of voclosporin exhibits a 30%, 40%, 50%, 60%, or 70% or greater decrease in the expression level of Trpm6 compared to baseline. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater decrease in the expression level of Trpm6 compared to baseline.

[0217] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30%, 40%, 50%, 60%, or 70% or greater increase in the expression level of the transient receptor potential cation channel subfamily M Member 6 (Trpm6) gene, as assessed after receiving the voclosporin, compared to the expression level of the transient receptor potential cation channel subfamily M Member 6 (Trpm6) gene, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30% or greater increase in the expression level of the transient receptor potential cation channel subfamily M Member 6 (Trpm6) gene, as assessed after receiving the voclosporin, compared to the expression level of the transient receptor potential cation channel subfamily M Member 6 (Trpm6) gene, as assessed after receiving the first CNI, but before receiving voclosporin.

[0218] In some embodiments, the subject selected for administration of voclosporin exhibits a 30%, 40%, 50%, 60%, or 70% or greater decrease in the expression level of the cyclin and CBS domain divalent metal cation transporter mediator 2 (Cnnm2) gene, as assessed after receiving the first CNI, compared to a baseline expression level of Cnnm2as assessed prior to receiving the first CNI. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater decrease in the expression level of the cyclin and CBS domain divalent metal cation transporter mediator 2 (Cnnm2) gene, as assessed after receiving the first CNI, compared to a baseline expression level of Cnnm2as assessed prior to receiving the first CNI. In some embodiments, the subject selected for administration of voclosporin exhibits a 30%, 40%, 50%, 60%, or 70% or greater decrease in the expression level of Cnnm2 compared to baseline. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater decrease in the expression level of Cnnm2 compared to baseline.

[0219] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30%, 40%, 50%, 60%, or 70% or greater increase in the expression level of the cyclin and CBS domain divalent metal cation transporter mediator 2 (Cnnm2) gene, as assessed after receiving the voclosporin, compared to the expression level of the cyclin and CBS domain divalent metal cation transporter mediator 2 (Cnnm2) gene, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30% or greater increase in the expression level of the cyclin and CBS domain divalent metal cation transporter mediator 2 (Cnnm2) gene, as assessed after receiving the voclosporin, compared to the expression level of the cyclin and CBS domain divalent metal cation transporter mediator 2 (Cnnm2) gene, as assessed after receiving the first CNI, but before receiving voclosporin.

[0220] In some embodiments, the subject selected for administration of voclosporin exhibits a 30%, 40%, 50%, 60%, or 70% or greater decrease in the expression level of the epidermal growth factor (Egf) gene, as assessed after receiving the first CNI, compared to a baseline expression level of Egfas assessed prior to receiving the first CNI. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater decrease in the expression level of the epidermal growth factor (Egf) gene, as assessed after receiving the first CNI, compared to a baseline expression level of Egfas assessed prior to receiving the first CNI. In some embodiments, the subject selected for administration of voclosporin exhibits a 30%, 40%, 50%, 60%, or 70% or greater decrease in the expression level of Egf compared to baseline. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater decrease in the expression level of Egf compared to baseline.

[0221] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30%, 40%, 50%, 60%, or 70% or greater increase in the expression level of the epidermal growth factor (Egf) gene, as assessed after receiving the voclosporin, compared to the expression level of the epidermal growth factor (Egf) gene, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30% or greater increase in the expression level of the epidermal growth factor (Egf) gene, as assessed after receiving the voclosporin, compared to theexpression level of the epidermal growth factor (Egf) gene, as assessed after receiving the first CNI, but before receiving voclosporin.

[0222] In some embodiments, the subject selected for administration of voclosporin exhibits a 30%, 40%, 50%, 60%, or 70% or greater decrease in the expression level of the calcium channel TRPV5 gene, as assessed after receiving the first CNI, compared to a baseline expression level of Trpv5as assessed prior to receiving the first CNI. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater decrease in the expression level of the calcium channel TRPV5 gene, as assessed after receiving the first CNI, compared to a baseline expression level of Trpv5as assessed prior to receiving the first CNI. In some embodiments, the subject selected for administration of voclosporin exhibits a 30%, 40%, 50%, 60%, or 70% or greater decrease in the expression level of Trpv5 compared to baseline. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater decrease in the expression level of Trpv5 compared to baseline.

[0223] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30%, 40%, 50%, 60%, or 70% or greater increase in the expression level of the calcium channel TRPV5 gene, as assessed after receiving the voclosporin, compared to the expression level of the calcium channel TRPV5 gene, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30% or greater increase in the expression level of the calcium channel TRPV5 gene, as assessed after receiving the voclosporin, compared to the expression level of the calcium channel TRPV5 gene, as assessed after receiving the first CNI, but before receiving voclosporin.

[0224] In some embodiments, the subject selected for administration of voclosporin exhibits a 30%, 40%, 50%, 60%, or 70% or greater decrease in the expression level of the solute carrier family 8 member Al (Slc8Al) gene, as assessed after receiving the first CNI, compared to a baseline expression level of Slc8alas assessed prior to receiving the first CNI. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater decrease in the expression level of the solute carrier family 8 member Al (Slc8Al) gene, as assessed after receiving the first CNI, compared to a baseline expression level of Slc8alas assessed prior to receiving the first CNI. In some embodiments, the subject selectedfor administration of voclosporin exhibits a 30%, 40%, 50%, 60%, or 70% or greater decrease in the expression level of Slc8al compared to baseline. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater decrease in the expression level of Slc8al compared to baseline.

[0225] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30%, 40%, 50%, 60%, or 70% or greater increase in the expression level of the solute carrier family 8 member Al (Slc8Al) gene, as assessed after receiving the voclosporin, compared to the expression level of the solute carrier family 8 member Al (Slc8Al) gene, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30% or greater increase in the expression level of the solute carrier family 8 member Al (Slc8Al) gene, as assessed after receiving the voclosporin, compared to the expression level of the solute carrier family 8 member Al (Slc8Al) gene, as assessed after receiving the first CNI, but before receiving voclosporin.

[0226] In some embodiments, the subject selected for administration of voclosporin exhibits a 30%, 40%, 50%, 60%, or 70% or greater decrease in the expression level of the calbindin 1 (Calbl) gene, as assessed after receiving the first CNI, compared to a baseline expression level of Calbl as assessed prior to receiving the first CNI. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater decrease in the expression level of the calbindin 1 (Calbl) gene, as assessed after receiving the first CNI, compared to a baseline expression level of Calbl as assessed prior to receiving the first CNI. In some embodiments, the subject selected for administration of voclosporin exhibits a 30%, 40%, 50%, 60%, or 70% or greater decrease in the expression level of Calbl compared to baseline. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater decrease in the expression level of Calbl compared to baseline.

[0227] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30%, 40%, 50%, 60%, or 70% or greater increase in the expression level of the calbindin 1 (Calbl) gene, as assessed after receiving the voclosporin, compared to the expression level of the calbindin 1 (Calbl) gene, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30% or greater increase in the expression level of the calbindin 1 (Calbl) gene, as assessed after receivingthe voclosporin, compared to the expression level of the calbindin 1 (Calbl) gene, as assessed after receiving the first CNI, but before receiving voclosporin.

[0228] In some embodiments, the subject selected for administration of voclosporin has a tubular dysfunction involving hypophosphatemia. In some embodiments, the subject selected for administration of voclosporin exhibits a 10% or greater, 15% or greater, 20% or greater, 30% or greater, 40% or greater or 50% or greater decrease in serum phosphate levels as assessed after receiving the first CNI, compared to a baseline serum phosphate level. In some embodiments, the subject selected for administration of voclosporin exhibits a 10% decrease in serum phosphate levels as assessed after receiving the first CNI, compared to a baseline serum phosphate level.

[0229] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 10% or greater, 15% or greater, 20% or greater, 30% or greater, 40% or greater or 50% or greater increase in serum phosphate levels, as assessed after receiving the voclosporin, compared to the serum phosphate level, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 10% or greater increase in serum phosphate levels, as assessed after receiving the voclosporin, compared to the serum phosphate level, as assessed after receiving the first CNI, but before receiving voclosporin.

[0230] In some embodiments, the subject selected for administration of voclosporin demonstrates a lower natriuretic response. In some embodiments, the subject selected for administration of voclosporin exhibits a 10% or greater, 15% or greater, 20% or greater, 30% or greater, 40% or greater or 50% or greater decrease in natriuretic response as assessed after receiving the first CNI, compared to a baseline natriuretic response. In some embodiments, the subject selected for administration of voclosporin demonstrates a lower natriuretic response. In some embodiments, the subject selected for administration of voclosporin exhibits a 10% or greater decrease in natriuretic response as assessed after receiving the first CNI, compared to a baseline natriuretic response.

[0231] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 10% or greater, 15% or greater, 20% or greater, 30% or greater, 40% or greater or 50% or greater increase in natriuretic response, as assessed after receiving the voclosporin, compared to the natriuretic response, as assessed after receivingthe first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 10% or greater increase in natriuretic response, as assessed after receiving the voclosporin, compared to the natriuretic response, as assessed after receiving the first CNI, but before receiving voclosporin.

[0232] In some embodiments, the subject selected for administration of voclosporin demonstrates a lower chloriuretic response. In some embodiments, the subject selected for administration of voclosporin exhibits a 10% or greater, 15% or greater, 20% or greater, 30% or greater, 40% or greater or 50% or greater decrease in chloriuretic response as assessed after receiving the first CNI, compared to a baseline chloriuretic response. In some embodiments, the subject selected for administration of voclosporin demonstrates a lower chloriuretic response. In some embodiments, the subject selected for administration of voclosporin exhibits a 10% or greater decrease in chloriuretic response as assessed after receiving the first CNI, compared to a baseline chloriuretic response.

[0233] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 10% or greater, 15% or greater, 20% or greater, 30% or greater, 40% or greater or 50% or greater increase in chloriuretic response, as assessed after receiving the voclosporin, compared to the chloriuretic response, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 10% or greater increase in chloriuretic response, as assessed after receiving the voclosporin, compared to the chloriuretic response, as assessed after receiving the first CNI, but before receiving voclosporin.

[0234] In some embodiments, the subject selected for administration of voclosporin has a tubular dysfunction involving hypertension. In some embodiments, the subject selected for administration of voclosporin exhibits a 10% or greater, 15% or greater, 20% or greater, 30% or greater, 40% or greater or 50% or greater increase in blood pressure as assessed after receiving the first CNI, compared to a baseline blood pressure. In some embodiments, the subject selected for administration of voclosporin exhibits a 10% increase in blood pressure as assessed after receiving the first CNI, compared to a baseline blood pressure.

[0235] In some embodiments, the subject selected for administration of voclosporin exhibits a 10% or greater, 15% or greater, 20% or greater, 30% or greater, 40% or greater or50% or greater increase in the plasma endothelin-1 level, as assessed after receiving the first CNI, compared to a baseline plasma endothelin-1 level. In some embodiments, the subject selected for administration of voclosporin exhibits a 10% or greater increase in the plasma endothelin-1 level, as assessed after receiving the first CNI, compared to a baseline plasma endothelin-1 level.

[0236] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 10% or greater, 15% or greater, 20% or greater, 30% or greater, 40% or greater or 50% or greater decrease in the plasma endothelin-1 level, as assessed after receiving the voclosporin, compared to the plasma endothelin-1 level, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 10% or greater decrease in the plasma endothelin-1 level, as assessed after receiving the voclosporin, compared to the plasma endothelin-1 level, as assessed after receiving the first CNI, but before receiving voclosporin.

[0237] In some embodiments, the subject selected for administration of voclosporin exhibits a 10% or greater, 15% or greater, 20% or greater, 30% or greater, 40% or greater or 50% or greater decrease in the expression level of cyclo-oxygenase 2, as assessed after receiving the first CNI, compared to a baseline expression level of cyclo-oxygenase 2. In some embodiments, the subject selected for administration of voclosporin exhibits a 10% or greater decrease in the expression level of cyclo-oxygenase 2, as assessed after receiving the first CNI, compared to a baseline expression level of cyclo-oxygenase 2.

[0238] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 10% or greater, 15% or greater, 20% or greater, 30% or greater, 40% or greater or 50% or greater increase in the expression level of cyclo-oxygenase 2, as assessed after receiving the voclosporin, compared to the expression level of cyclooxygenase 2, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 10% or greater increase in the expression level of cyclo-oxygenase 2, as assessed after receiving the voclosporin, compared to the expression level of cyclooxygenase 2, as assessed after receiving the first CNI, but before receiving voclosporin.

[0239] In some embodiments, the subject selected for administration of voclosporin has a tubular dysfunction involving metabolic acidosis. In some embodiments, the subject selectedfor administration of voclosporin exhibits a 10% or greater, 15% or greater, 20% or greater, 30% or greater, 40% or greater or 50% or greater increase in metabolic acidosis as assessed after receiving the first CNI, compared to a baseline level of metabolic acidosis. In some embodiments, the subject selected for administration of voclosporin exhibits a 10% increase in metabolic acidosis as assessed after receiving the first CNI, compared to a baseline level of metabolic acidosis.

[0240] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 10% or greater, 15% or greater, 20% or greater, 30% or greater, 40% or greater or 50% or greater decrease in the level metabolic acidosis, as assessed after receiving the voclosporin, compared to the level of metabolic acidosis, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 10% or greater decrease in the level metabolic acidosis, as assessed after receiving the voclosporin, compared to the level of metabolic acidosis, as assessed after receiving the first CNI, but before receiving voclosporin.D. Renal Biopsy

[0241] Kidney biopsy of CNI-induced chronic nephrotoxicity reveals primary endothelial damage (shown for example, by obliterative arteriolopathy), vasoconstriction, ischemic collapse or scarring of the glomeruli, vacuolization of the tubules and / or global and focal segmental glomerulosclerosis. Moreover, interstitial fibrosis and tubular atrophy (IFTA) occur in focal areas. See e.g., Bulow et al., Journal of Histochemistry & Cytochemistry, 2019, 67(9): 643-661 and Naesens et al., Journal of the American Society of Nephrology, 2009, 4:481-508. Chronic nephrotoxicity can also result in a steady decline in glomerular filtration rate (GFR).

[0242] In some embodiments, one or more indicators of drug-induced nephrotoxicity are assessed based on one or more renal biopsies. Kidney biopsies reveal an obliterative arteriolopathy, which is indicative of primary endothelial damage, for chronic legacy drug- induced nephrotoxicity. Nephrotoxicity kidney biopsies can also demonstrate vasoconstriction, ischemic collapse or scarring of the glomeruli, vacuolization of the tubules, global and focal segmental glomerulosclerosis, and focal areas of interstitial fibrosis and tubular atrophy (IFTA). In some embodiments, interstitial fibrosis and tubular atrophy are observed together. In some embodiments, subjects with proteinuric remission can havehistologic activity. In some embodiments, subjects without proteinuric remission can have histologic activity. In some embodiments, renal biopsies are collected at various time points. In some aspects, the subject is assessed for repeat renal biopsies, including a renal biopsy collected before administration of the first CNI and after beginning administration of the first CNI.

[0243] Biopsies can be assessed using light microscopy, immunofluorescent microscopy or electron microscopy. Collected renal biopsies can be assessed by hematoxylin and eosin staining (H&E), periodic acid-Schiff (PAS), silver and trichrome stains and collagen III immunohistochemistry. Renal biopsies can also be stained for immunofluorescence with, including but not limited to, C3, C4, C5, Clq, IgG, IgM, and IgA. Renal biopsies can be graded semi-quantitatively using the following categories: Grade 0: < 5%; Grade 1: 5-25%; Grade 2: 25-< 50%; Grade 3: > 50%. The categories represent the percentage of non-scarred cortical area involved by mononuclear cell infiltrate and are analogous to the Banff interstitial inflammation scores for kidney allograft rejection. The tri chrome stain is used to aid in the identification of fibrosis.

[0244] In some embodiments, renal biopsies collected at baseline and after administration of the first CNI can be examined to identify the presence of interstitial fibrosis and tubular atrophy. Interstitial fibrosis is identified as the accumulation of collagen and related molecules in the interstitium. Tubular atrophy is identified by small tubules with cells with pale cytoplasm or dilated, thin tubules.

[0245] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises interstitial fibrosis and tubular atrophy, or any assessments or indicators associated with or indicative of interstitial fibrosis and tubular atrophy. In some embodiments, the methods disclosed herein includes assessing the interstitial fibrosis and tubular atrophy of the subject by renal biopsies compared to a baseline level, and if interstitial fibrosis and tubular atrophy is observed in a more than a predetermined percentage of cortical area, compared to baseline levels, selecting the subject for voclosporin administration.

[0246] In some embodiments, the predetermined percentage is any one of 0%, 1%, 2%, 5%, 10%, 15%, 20%, 25%, or 50%, or any percentage there between. In some embodiments, the predetermined percentage is any one of about 0% to 5%, about 5% to about 25%, about 25% to about 50%, or about 50% to about 99%. In some embodiments, the predetermined percentage is any one of < 5%; 5-25%; 25- < 50%; or > 50%. In some embodiments, thepredetermined percentage is about < 5%. In some embodiments, the predetermined percentage is about 5%. In some embodiments, the predetermined percentage is about > 5%.In some embodiments, interstitial fibrosis and tubular atrophy is determined by involved by mononuclear cell infiltrate in non-scarred cortical area, and are analogous to the Banff interstitial inflammation scores for kidney allograft rejection. In some embodiments, the percentage of non-scarred cortical area involved by mononuclear cell infiltrate is assessed by hematoxylin and eosin staining (H&E), periodic acid-Schiff (PAS), silver and trichrome stains and collagen III immunohistochemistry and are graded semi-quantitatively using the following categories: Grade 0: < 5%; Grade 1: 5-25%; Grade 2: 25-< 50%; Grade 3: > 50%. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits interstitial fibrosis and tubular atrophy in observed in > 5% in cortical area after receiving the first CNI, based on the renal biopsies.

[0247] In some embodiments, renal biopsies collected at baseline and after administration of the first CNI can be assessed for renal injury, including glomerular injury. In some embodiments, renal biopsies collected at baseline and after administration of the first CNI can be assessed for glomerular injury, such as global glomerulosclerosis. In some embodiments, global glomerulosclerosis is identified by the presence of arteriolar hyalinosis, arteriolopathy, secondary glomerular ischemia, and / or atubular glomeruli.

[0248] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises glomerular injury, or any assessments or indicators associated with or indicative of glomerular injury. In some embodiments, the methods and uses involve assessing the presence of glomerular injury of the subject by renal biopsies compared to a baseline level, and if glomerular injury is present, compared to baseline levels, selecting the subject for voclosporin administration.

[0249] In some embodiments, renal biopsies collected at baseline and after administration of the first CNI can be assessed for medial arteriolar hyalinosis. The presence of nodular hyaline deposits in the media of afferent arterioles is identified by the replacement of necrotic smooth muscle cells with focal or circular lumpy protein (hyaline) deposits at the periphery of the wall of afferent arterioles. Further evaluation includes assessment of the narrowing of the vascular lumen, which is negatively associated with positive renal outcome.

[0250] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises medial arteriolar hyalinosis, or any assessments or indicators associated with orindicative of medial arteriolar hyalinosis. In some embodiments, the methods and uses involve assessing the presence of medial arteriolar hyalinosis of the subject by renal biopsies compared to a baseline level, and if medial arteriolar hyalinosis is present, compared to baseline levels, selecting the subject for administration of voclosporin In some embodiments, medial arteriolar hyalinosis is identified by the replacement of necrotic smooth muscle cells with focal, circular lumpy protein (hyaline) deposits at the periphery of the wall of afferent arterioles, and the narrowing of the vascular lumen. In some embodiments, medial arteriolar hyalinosis is identified by the replacement of necrotic smooth muscle cells with focal, circular lumpy protein (hyaline) deposits at the periphery of the wall of afferent arterioles, or the narrowing of the vascular lumen. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits medial arteriolar hyalinosis after receiving the first CNI, based on the renal biopsies. In some aspects, medial arteriolar hyalinosis is identified by the replacement of necrotic smooth muscle cells with focal, circular lumpy protein (hyaline) deposits at the periphery of the wall of afferent arterioles, and / or the narrowing of the vascular lumen.

[0251] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises atubular glomeruli, or any assessments or indicators associated with or indicative of atubular glomeruli. In some embodiments, renal biopsies collected at baseline and after administration of the first CNI can be assessed for atubular glomeruli. The presence of atubular glomeruli is characterized by the presence of glomeruli that are disconnected from the proximal tubule. Atubular glomeruli are also identified by the presence of periglomerular fibrosis (capsular fibrosis), or by the presence of severely contracted glomeruli within an enlarged glomerular cyst.

[0252] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises glomerulosclerosis, or any assessments or indicators associated with or indicative of glomerulosclerosis. In some embodiments, renal biopsies collected at baseline and after administration of the first CNI can be assessed for focal segmental glomerulosclerosis. Focal segmental glomerulosclerosis lesions are identified by the presence of sclerosis in parts of at least one glomerulus, and are identified as approximately 12.5 percent of the total glomerular volume. In some aspects, renal injury comprises global and segmental glomerulosclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis. In some embodiments, renal injury comprises global and segmental glomerulosclerosis, tubular atrophy, interstitial fibrosis, orarteriosclerosis. In some examples, renal injury is present when the total renal chronicity score is > 1. To determine renal injury, global and segmental glomerulosclerosis is scored from 0 to 3, tubular atrophy from 0 to 3, interstitial fibrosis from 0 to 3 and arteriosclerosis from 0 to 1. The scores are then added (total renal chronicity score) to grade the overall severity of the chronic lesions into minimal (0-1 total score), mild (2-4 total score), moderate (5-7 total score) and severe (> 8 total score). In some embodiments, renal injury is determined to be present when total renal chronicity score is greater than any one of: 0, 1, 2, 3, 4, 5, 6, 7, 8. In some embodiments, renal injury is determined to be present when total renal chronicity score is any one of: about 1, about 2 to about 4, about 5 to about 7, or about 8 to about 10. In some embodiments, renal injury comprises a mild (2-4 total score) glomerular injury. In some embodiments, renal injury comprises a moderate (5-7 total score) glomerular injury. In some embodiments, renal injury comprises a severe (> 8 total score) glomerular injury.

[0253] In some aspects, the subject is selected for administration of voclosporin if the subject exhibits renal injury, including medial arteriolar hyalinosis after receiving the first CNI, based on the renal biopsies. In some aspects, renal injury is identified by the presence of global and segmental glomerulosclerosis, tubular atrophy, interstitial fibrosis, and / or arteriosclerosis; and / or the total renal chronicity score of > 1.

[0254] In some embodiments, National Institutes of Health Activity Index (NIH-AI), the National Institutes of Health Chronicity Index (NIH-CI), and the Tubulointerstitial Activity Index (TIAI) can be used. In some embodiments, renal biopsies collected at baseline and after administration of the first CNI can be assessed to determine a NIH-AI, a NIH-CI, or a TIAI.

[0255] In some embodiments, the National Institutes of Health Activity Index (NIH-AI) is used to assess disease activity, including histologic measures of inflammation. In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises an increase in NIH-AI, or any assessments or indicators associated with or indicative of an increase in NIH-AI. In some embodiments, the NIH-AI score is determined based on component scores that can include endocapillary hypercellularity, neutrophils and karyorrhexis, hyaline deposits and wire loops, fibrinoid necrosis, cellular or fibrocellular crescents, and interstitial inflammation. In some aspects, the NIH-AI is calculated based on a total score of the component scores. In some aspects, the NIH-AI comprises scoring thepercentage of glomeruli that display each feature described below in the biopsy on a scale of 0 to 3 (a score of 0 = not present, 1 = < 25% glomeruli, 2 = 25-50% glomeruli, and 3 indicating > 50% glomeruli).

[0256] In some embodiments, a component score of the NIH-AI includes endocapillary hypercellularity score, on a scale of 0-3. In some embodiments, a component score of the NIH-AI includes neutrophils and karyorrhexis score, on a scale of 0-3. In some embodiments, a component score of the NIH-AI includes hyaline deposits and wire loops score, on a scale of 0-3. In some embodiments, a component score of the NIH-AI includes fibrinoid necrosis score, on a scale of (0-3) x 2. In some embodiments, a component score of the NIH-AI includes cellular or fibrocellular crescents score, on a scale of (0-3) x 2. Fibrinoid necrosis and crescents are weighted twice as they have a worse impact on prognosis. In some embodiments, a component score of the NIH-AI includes interstitial inflammation score, on a scale of 0-3.

[0257] In some embodiments, the NIH-AI includes one or more of the component scores and a total score out of 24 is used. In some embodiments, the total NIH-AI score includes all of the component scores and a total score out of 24 is used. The score range is 0-24, with 0 considered inactive. A high NIH-AI value (> 6) is considered a high level of renal damage.

[0258] In some aspects, the subject is selected for administration of voclosporin if the subject exhibits an increase in the National Institutes of Health Activity Index (NIH-AI) from a renal biopsy as assessed after receiving the first CNI, compared to a baseline NIH-AI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a 10%, 20%, 30%, 40%, or 50% or greater increase in the NIH-AI as assessed after receiving the first CNI, compared to a baseline NIH-AI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a 10% or greater increase in the NIH-AI as assessed after receiving the first CNI, compared to a baseline NIH-AI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a 20% or greater increase in the NIH-AI as assessed after receiving the first CNI, compared to a baseline NIH-AI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a 30% or greater increase in the NIH-AI as assessed after receiving the first CNI, compared to a baseline NIH-AI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a 40% or greater increase in the NIH-AI as assessed after receiving the first CNI, compared to a baseline NIH-AI. In some aspects,the subject is selected for administration of voclosporin if the subject exhibits a 50% or greater increase in the NIH-AI as assessed after receiving the first CNI, compared to a baseline NIH-AI.

[0259] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 10%, 20%, 30%, 40%, or 50% or greater decrease in the NIH-AI, as assessed after receiving the voclosporin, compared to the NIH-AI, as assessed after receiving the first CNI, but before receiving voclosporin.

[0260] In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or higher after receiving the first CNI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 3 or higher after receiving the first CNI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 4 or higher after receiving the first CNI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 5 or higher after receiving the first CNI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 6 or higher after receiving the first CNI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 7 or higher after receiving the first CNI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 8 or higher after receiving the first CNI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 9 or higher after receiving the first CNI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 10 or higher after receiving the first CNI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 11 or higher after receiving the first CNI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI score of 12 or higher after receiving the first CNI.

[0261] In some embodiments, the National Institutes of Health Chronicity Index (NIH- CI) is used to assess chronicity, including irreversible kidney damage and scarring associated with end-stage kidney disease. In some embodiments, the one or more indicators of drug- induced nephrotoxicity comprises an increase in NIH-CI, or any assessments or indicators associated with or indicative of an increase in NIH-CI. In some aspects, the NIH-CI score isdetermined based on component scores that can include global and segmental glomerulosclerosis, fibrous crescents, tubular atrophy, or interstitial fibrosis. In some aspects, the NIH-CI is calculated based on a total score of the component scores.

[0262] In some aspects, a component score of the NIH-CI includes global and segmental glomerulosclerosis score, on a scale of 0-3. In some embodiments, a component score of the NIH-CI includes fibrous crescents score, on a scale of 0-3. In some embodiments, a component score of the NIH-CI includes tubular atrophy score, on a scale of 0-3. In some embodiments, a component score of the NIH-CI includes interstitial fibrosis score, on a scale of 0-3.

[0263] In some embodiments, the NIH-CI includes one or more of the component scores and a total score out of 12 is used. In some embodiments, the total NIH-CI score includes all of the component scores and a total score out of 12 is used. In some aspects, the component scores are added (total renal chronicity score) to grade the overall severity of the chronic lesions into minimal (0-1 total score), mild (2-4 total score), moderate (5-7 total score) and severe (> 8 total score), indicators of NIH-CI include the total percentage of global glomerulosclerosis, fibrous crescents, tubular atrophy, and interstitial fibrosis. The NIH-CI score range is 0 - 12, with 0 representing no chronicity. A high NIH-CI value (> 3) is correlated with progression to renal failure.

[0264] In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a 10%, 20%, 30%, 40%, or 50% or greater increase in the NIH-CI as assessed after receiving the first CNI, compared to a baseline NIH-CI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits an increase in the National Institutes of Health Chronicity Index (NIH-CI) from a renal biopsy as assessed after receiving the first CNI, compared to a baseline NIH-CI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a 10% or greater increase in the NIH-CI as assessed after receiving the first CNI, compared to a baseline NIH-CI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a 20% or greater increase in the NIH-CI as assessed after receiving the first CNI, compared to a baseline NIH-CI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a 30% or greater increase in the NIH-CI as assessed after receiving the first CNI, compared to a baseline NIH-CI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a 40% or greater increase in the NIH-CIas assessed after receiving the first CNI, compared to a baseline NIH-CI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a 50% or greater increase in the NIH-CI as assessed after receiving the first CNI, compared to a baseline NIH-CI.

[0265] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 10%, 20%, 30%, 40%, or 50% or greater decrease in the NIH-CI, as assessed after receiving the voclosporin, compared to the NIH-CI, as assessed after receiving the first CNI, but before receiving voclosporin.

[0266] In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-CI score of 3, 4, 5, 6 or higher after receiving the first CNI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH- CI score of 3 or higher after receiving the first CNI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-CI score of 4 or higher after receiving the first CNI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-CI score of 5 or higher after receiving the first CNI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a NIH-CI score of 6 or higher after receiving the first CNI.

[0267] An exemplary scoring system for NIH-AI and NIH-CI is set forth in Table 1 below (see, e.g., Bajema et al. Kidney Int. 2018;93(4):789-796).Table 1

[0268] In some embodiments, the methods and uses involve assessing one or more of the National Institutes of Health Activity Index (NIH-AI), the National Institutes of Health Chronicity Index (NIH-CI), and the Tubulointerstitial Activity Index (TIAI) of the subject by renal biopsies compared to a baseline level, and if the NIH-AI, NIH-CI, and / or TIAI are outside of predetermined ranges, compared to baseline levels, selecting the subject for voclosporin administration. In some embodiments, the predetermined range of NIH-AI is about any one of 0 to 1, 0 to 2, 0 to 3, 0 to 4, 0 to 5, 0 to 6, 0 to 7, 0 to 8, 0 to 9, 0 to 10, 0 to 11, 0 to 12, 0 to 13, 0 to 14, 0 to 15, 0 to 16, 0 to 17, 0 to 18, 0 to 19 or 0 to 20. In some embodiments, the predetermined range of NIH-AI is any one of <1, < 2, <3, <4, <5, <6, <7, <8, <9, <10, <11, <12, <13, <14, <15, <16, <17, <18, <19, or < 20. In some embodiments, the predetermined range of NIH-AI is about 0 to6. In some embodiments, the predetermined range of NIH-CI is about any one of 0 to 1, 0 to 2, 0 to 3, 0 to 4, 0 to 5, 0 to 6, 0 to 7, 0 to 8, 0 to 9, or 0 to 10. In some embodiments, the predetermined range of NIH-CI is any one of <1, < 2, <3, <4, <5, <6, <7, <8, <9, or <10. In some embodiments, the predetermined range of NIH-CI is about 0 to3. In some embodiments, the predetermined range of TIAI is about any one of 0 to 1, 0 to 2, 0 to 3, 0 to 4, 0 to 5, 0 to 6, 0 to 7, 0 to 8, 0 to 9, 0 to 10, 0 to 11, 0 to 12, 0 to 13, 0 to 14, or 0 to 15. In some embodiments, the predetermined range of NIH-AI is any one of <1, < 2, <3, <4, <5, <6, <7, <8, <9, <10, <11, <12, <13, <14, or <15. In some embodiments, the predetermined range of TIAI is about 0 to 5. In some embodiments, the predetermined range of NIH-AI is about 0 to 6, or the predetermined range of NIH-CI is about 0 to 3, and / or the predetermined range of TIAI is about 0 to 5. In some embodiments, the predetermined range of NIH-AI is 0 to 6, and the predetermined range of NIH-CI is 0 to 3, or the predetermined range of TIAI is 0 to 5.

[0269] For TIAI, tubular cell pyknosis, nuclear activation, necrosis, flattening, macrophages in the tubular lumens, epithelial cells in the tubular lumens, and interstitial inflammation are evaluated. The TIAI score range is 0 to 21, with 0 representing no interstitial activity. In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises an increase in TIAI, or any assessments or indicators associated with or indicative of an increase in TIAI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a 10% or greater increase in the TIAI as assessed after receiving the first CNI, compared to a baseline TIAI. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a TIAI score of 3 or higher after receiving the first CNI.

[0270] In some embodiments, renal biopsies collected at baseline and after administration of the first CNI can be assessed for juxtaglomerular apparatus (JGA) hyperplasia. Renal biopsies are stained with Masson and immunoperoxidase stains, and immunohistochemical analysis is performed. Samples are further analyzed by electron microscopy. JGA hyperplasia is assessed as enlargement of the juxtaglomerular apparatus components, including the vascular components (portions of afferent and efferent arterioles), the mesangial cell components (modified extraglomerular and intraglomerular smooth muscle cells), and the tubular components (the macula densa), as well as the presence of intracellular renin granules.

[0271] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises presence of juxtaglomerular apparatus (JGA) hyperplasia, or any assessments or indicators associated with or indicative of JGA hyperplasia. In some embodiments, the method disclosed herein further includes assessing the presence of JGA hyperplasia of the subject by renal biopsies compared to a baseline level, and if JGA hyperplasia is present, compared to baseline levels, selecting the subject for voclosporin administration. In some examples, JGA hyperplasia includes enlargements of juxtaglomerular apparatus components comprising one or more of: the vascular components, the mesangial cell components, the tubular components (the macula densa), and the presence of intracellular renin granules. In some examples, the JGA hyperplasia includes enlargements of juxtaglomerular apparatus components comprising one or more of: the vascular components, the mesangial cell components, the tubular components (the macula densa), or the presence of intracellular renin granules.

[0272] In some embodiments, renal biopsies collected at baseline and after administration of the first CNI can be assessed for tubular microcalcifications. In some embodiments, histological slides of undecalcified formalin (4%) fixed, paraffin-embedded biopsies are analyzed with haematoxylin and eosin staining (H&E) and periodic acid Schiff (PAS) stains, as well as von Kossa and Alizarin stains for visualization of calcium phosphate depositions. Electron microscopy is used to further identify deposition of calcium in renal tubules. The density of microcalcifications is evaluated as the number of calcification foci per square millimeter of biopsy, and calculated by dividing the total number of calcification foci found in the biopsy by the total area of the biopsy measured on the slide (foci per square millimeter).

[0273] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises tubular microcalcification, or any assessments or indicators associated with or indicative of tubular microcalcification. In some embodiments, the method disclosed herein further includes assessing the presence of tubular microcalcifications of the subject by renal biopsies compared to a baseline level, and if tubular microcalcifications is present, compared to baseline levels, selecting the subject for administration of voclosporin.

[0274] In some embodiments, renal biopsies collected at baseline and after administration of the first CNI can be assessed for P-gly coprotein (P-gp) expression, to determine if the renal biopsies reveal the loss of expression of P-gp outside of a predetermined range. P- gly coprotein expression is analyzed by the staining of renal biopsies using anti-P- gly coprotein antibodies. P-gly coprotein expression in glomeruli and tubular epithelial cells is scored semi-quantitatively according to the intensity and distribution. The classification includes: normal = 0 point, P-gp expression loss in < 10% of tubules placed in the cortical area; mild loss = 1 point, P-gp expression loss in 10% to 24% of tubuli in the cortical area; moderate loss = 2 points, P-gp expression loss in 25% to 50% of tubuli in the cortical area; severe loss = 3 points, P-gp expression loss in > 50% of tubuli in the cortical area. A decrease in expression of P-gly coprotein is associated with renal pathology. In some embodiments, P-gly coprotein expression classification comprises a mild loss. In some embodiments, P-gly coprotein expression classification comprises a moderate loss. In some embodiments, P-gly coprotein expression classification comprises a severe loss.

[0275] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises P-gp expression, or any assessments or indicators associated with or indicative of P-gp expression. In some embodiments, the method disclosed herein further includes assessing the P-gp expression of the subject by renal biopsies compared to a baseline level, and if loss of expression of P-gp is more than a predetermined value, compared to baseline levels, selecting the subject for administration of voclosporin In some examples, the predetermined value for loss of expression of P-gp is 10% loss of P-gp expression in tubules in the cortical area. P-gly coprotein expression in glomeruli and tubular epithelial cells can be scored semi-quantitatively according to the intensity and distribution. The classification can include: normal = 0 point, P-gp expression loss in < 10% of tubules placed in the cortical area; mild loss = 1 point, P-gp expression loss in 10% to 24% of tubuli in the cortical area; moderate loss = 2 points, P-gp expression loss in 25% to 50% of tubuli in the cortical area;severe loss = 3 points, P-gp expression loss in > 50% of tubuli in the cortical area. In some embodiments, the predetermined value for loss of expression of P-gp is about 5% to about 50% loss of P-gp expression in tubules in the cortical area. In some embodiments, the predetermined value for loss of expression of P-gp is about any one of: 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% loss of P-gp expression in tubules in the cortical area. In some embodiments, the predetermined value for loss of expression of P-gp is any one of: about 1% to about 5%, about 5% to about 10%, about 10% to about 25%, about 25% to about 50%, or 50% or more loss of P-gp expression in tubules in the cortical area. In some examples, the predetermined value for loss of expression of P-gp is 10% loss of P-gp expression in tubules in the cortical area. In some embodiments, the subject is selected for administration of voclosporin if the subject exhibits a 10% or greater loss of P-gly coprotein (P-gp) expression as assessed after receiving the first CNI, compared to a baseline P-gp expression, based on the renal biopsies.

[0276] In some embodiments, renal biopsies collected at baseline and after administration of the first CNI can be assessed to determine a drug-induced nephrotoxicity score or a Banff Chronicity Score (BChS), to determine if the renal biopsies reveal a drug-induced nephrotoxicity score of a BChS outside of a predetermined range.

[0277] In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises Drug-induced nephrotoxicity and / or Banff scores, or any assessments or indicators associated with or indicative of Drug-induced nephrotoxicity and / or Banff scores. In some embodiments, the method disclosed herein further includes assessing the Drug-induced nephrotoxicity and / or Banff Scores of the subject by renal biopsies compared to a baseline level, and if the CNI Nephrotoxicity and / or Banff Scores are outside of predetermined ranges, compared to baseline levels, selecting the subject for administration of voclosporin. In some embodiments, the predetermined range of CNI Nephrotoxicity Score is about any one of 0 to 1, 0 to 2, 0 to 3, 0 to 4, 0 to 5, 0 to 6, 0 to 7, 0 to 8, 0 to 9, or 0 to 10. In some embodiments, the predetermined range of CNI Nephrotoxicity Score is about any one of <1, < 2, <3, <4, <5, <6, <7, <8, <9, or <10. In some embodiments, the predetermined range of Banff Score is about any one of 0 to 1, 0 to 2, 0 to 3, 0 to 4, 0 to 5, 0 to 6, 0 to 7, 0 to 8, 0 to 9, or 0 to 10. In some embodiments, the predetermined range of Banff Score is about any one of <1, < 2, <3, <4, <5, <6, <7, <8, <9, or <10. In some embodiments, the predetermined range of CNI Nephrotoxicity Score is 0 to 3, or the predetermined range of Banff Score is 0 to 3. In someaspects, the subject is selected for administration of voclosporin if the subject exhibits a Drug-induced nephrotoxicity score of Nephrotoxicity Score of 0 to 3 after receiving the first CNI, based on the renal biopsies. In some aspects, the subject is selected for administration of voclosporin if the subject exhibits a Banff score of 0 to 3 after receiving the first CNI, based on the renal biopsies.

[0278] For grading the severity of chronic changes, biopsies can be scored in a semi- quantitative manner. In some aspects, a CNI Nephrotoxicity score is evaluated based on six parameters that are graded on a scale of 0 to 3, resulting in a possible total score of 18. The six parameters include: (1) isometric tubular vacuolization (tv), (2) peripheral or medial arteriolar hyaline (ah), (3) striped interstitial fibrosis, (4) ischemic collapse of glomeruli, (5) juxtaglomerular apparatus hyperplasia, and (6) tubular dystrophic calcifications. To determine the Banff Chronicity Score (BChS), renal biopsies are analyzed for transplant glomerulopathy (eg), tubular atrophy (ct), interstitial fibrosis (ci), and chronic vascular changes (cv), and are graded on a scale of 0 to 3. The severity of renal pathology is categorized into mild, moderate, and severe. In some embodiments, renal pathology classification comprises a mild severity. In some embodiments, renal pathology classification comprises a moderate severity. In some embodiments, renal pathology classification comprises a severe severity.E. Drug-Drug Interactions

[0279] In some aspects, the subject is selected if the subject exhibits a drug-drug interaction with other drugs or immunosuppressants that are commonly administered together with a CNI, after administration of the first CNI. In some aspects, because many different immunosuppressants are commonly administered together, any negative effects on other immunosuppressants by legacy CNIs can lead to less effective treatment. In some aspects, if the subject that has been administered a legacy CNI as a first CNI in combination with another drug, and exhibits a drug-drug interaction, such as a reduction in blood levels of the other drug, the subject is selected for administration of voclosporin, which is observed to exhibit minimal drug-drug interaction and negative effects on the other drug.

[0280] In some embodiments, the one or more indicators of drug-drug interaction comprises a reduction of blood levels of mycophenolic acid (MPA) after previously receiving a first CNI in combination with my cophenolate mofetil (MMF) for immunosuppression, or any assessments or indicators associated with or indicative of a reduction in blood MPAlevels. In some embodiments, the methods and uses involve selecting a subject who exhibits a reduction of blood levels of MPA after previously receiving a first CNI in combination with MMF for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof. In some embodiments, the selected subject is administered voclosporin.

[0281] The active moiety of MMF is MPA. MPA is metabolized in the liver and becomes the inactive metabolite MPA glucuronide (MP AG). MP AG is excreted into bile by the multidrug resistance-associated protein 2 (MRP2). MP AG undergoes enterohepatic circulation and specifically is deconjugated back to MPA in the small intestine and reabsorbed back into circulation, contributing to MPA exposure (see Van Gelder et al., Nephrol Dial Transplant, 2022 37: 917-922).

[0282] Blood levels of MPA is determined as the maximum serum concentration (Cmax) or area under the concentration curve from time 0 to 12 h (AUC0-12). In some embodiments, the selected subject exhibits a 1.0-fold, 1.5-fold, 2.0-fold, 2.5-fold, or 3.0-fold or greater reduction in the blood levels of MPA, as assessed after receiving the first CNI, compared to a baseline blood level of MPA as assessed prior to receiving the first CNI. In some embodiments, the selected subject exhibits a 1.0-fold or greater reduction in the blood levels of MPA, as assessed after receiving the first CNI, compared to a baseline blood level of MPA. In some embodiments, the selected subject exhibits a 1.5-fold or greater reduction in the blood levels of MPA, as assessed after receiving the first CNI, compared to a baseline blood level of MPA. In some embodiments, the selected subject exhibits a 2.0-fold or greater reduction in the blood levels of MPA, as assessed after receiving the first CNI, compared to a baseline blood level of MPA.

[0283] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 1.0-fold, 1.5-fold, 2.0-fold, 2.5-fold, or 3.0-fold or greater increase in the blood levels of MPA, as assessed after receiving the voclosporin, compared to the blood level of MPA, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 1.0-fold or greater increase in the blood levels of MPA, as assessed after receiving the voclosporin, compared to the blood level of MPA, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 1.5-fold or greater increase in the blood levels of MPA, as assessedafter receiving the voclosporin, compared to the blood level of MPA, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 2.0-fold or greater increase in the blood levels of MPA, as assessed after receiving the voclosporin, compared to the blood level of MPA, as assessed after receiving the first CNI, but before receiving voclosporin.F. Serum Lipid Profiles

[0284] In some embodiments, the methods and uses involve assessing the level of one or more lipids of the subject compared to a baseline level, and if the level of the one or more lipid is outside of a predetermined range, selecting the subject for voclosporin administration. In some embodiments, the one or more indicators of dyslipidemia comprises an increase in serum lipids or an increase in inflammatory lipids, or any assessments or indicators associated with or indicative of an increase in any of the particular lipids described herein.

[0285] In some embodiments, the one or more lipids comprises ceramide (CER). In some embodiments, the one or more lipids comprises dihydroceramide (DCER). In some embodiments, the one or more lipids comprises monoacylglycerol (MAG). In some embodiments, the one or more lipids comprises saturated diacylglycerol. In some embodiments, the one or more lipids comprises lysophosphatidy choline. In some embodiments, the one or more lipids comprises phosphatidylinositol (PI). In some embodiments, the one or more lipids comprises sphingomyelin (SM). In some embodiments, the one or more lipids comprises triacylglycerol (TAG).

[0286] In some embodiments, the subject selected for administration of voclosporin exhibits a 15% or greater, 20% or greater, 25% or greater, or 30% or greater increase in the level of TAG, as assessed after receiving the first CNI, compared to a baseline level of TAG. In some embodiments, the subject selected for administration of voclosporin exhibits a 15% or greater increase in the level of TAG, as assessed after receiving the first CNI, compared to a baseline level of TAG. In some embodiments, the subject selected for administration of voclosporin exhibits a 20% or greater increase in the level of TAG, as assessed after receiving the first CNI, compared to a baseline level of TAG. In some embodiments, the subject selected for administration of voclosporin exhibits a 25% or greater increase in the level of TAG, as assessed after receiving the first CNI, compared to a baseline level of TAG. In some embodiments, the subject selected for administration of voclosporin exhibits a 30%or greater increase in the level of TAG, as assessed after receiving the first CNI, compared to a baseline level of TAG.

[0287] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15%, 20%, 25%, or 30% or greater decrease in the level of TAG, as assessed after receiving the voclosporin, compared to the level of TAG, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15% or greater decrease in the level of TAG, as assessed after receiving the voclosporin, compared to the level of TAG, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 20% or greater decrease in the level of TAG, as assessed after receiving the voclosporin, compared to the level of TAG, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 25% or greater decrease in the level of TAG, as assessed after receiving the voclosporin, compared to the level of TAG, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30% or greater decrease in the level of TAG, as assessed after receiving the voclosporin, compared to the level of TAG, as assessed after receiving the first CNI, but before receiving voclosporin.

[0288] In some embodiments, the subject selected for administration of voclosporin exhibits a 15%, 20%, 25%, or 30% or greater increase in the level of ceramides (CER), as assessed after receiving the first CNI, compared to a baseline level of CER. In some embodiments, the subject selected for administration of voclosporin exhibits a 15% or greater increase in the level of ceramides (CER), as assessed after receiving the first CNI, compared to a baseline level of CER. In some embodiments, the subject selected for administration of voclosporin exhibits a 20% or greater increase in the level of CER, as assessed after receiving the first CNI, compared to a baseline level of CER. In some embodiments, the subject selected for administration of voclosporin exhibits a 25% or greater increase in the level of CER, as assessed after receiving the first CNI, compared to a baseline level of CER. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater increase in the level of CER, as assessed after receiving the first CNI, compared to a baselinelevel of CER.

[0289] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15%, 20%, 25%, or 30% or greater decrease in the level of CER, as assessed after receiving the voclosporin, compared to the level of CER, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15% or greater decrease in the level of CER, as assessed after receiving the voclosporin, compared to the level of CER, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 20% or greater decrease in the level of CER, as assessed after receiving the voclosporin, compared to the level of CER, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 25% or greater decrease in the level of CER, as assessed after receiving the voclosporin, compared to the level of CER, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30% or greater decrease in the level of CER, as assessed after receiving the voclosporin, compared to the level of CER, as assessed after receiving the first CNI, but before receiving voclosporin.

[0290] In some of any embodiments, the one or more lipid is selected from one or more of total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol, and triglyceride. In some of any embodiments, the lipid is selected from one or more of total cholesterol, low density lipoprotein (LDL) cholesterol, and triglyceride.

[0291] In some embodiments, the subject selected for administration of voclosporin exhibits a 15%, 20%, 25%, or 30% or greater increase in the level of low density lipoprotein (LDL) cholesterol, as assessed after receiving the first CNI, compared to a baseline level of LDL. In some embodiments, the subject selected for administration of voclosporin exhibits a 15% or greater increase in the level of low density lipoprotein (LDL) cholesterol, as assessed after receiving the first CNI, compared to a baseline level of LDL. In some embodiments, the subject selected for administration of voclosporin exhibits a 20% or greater increase in the level of low density LDL cholesterol, as assessed after receiving the first CNI, compared to a baseline level of LDL. In some embodiments, the subject selected for administration ofvoclosporin exhibits a 25% or greater increase in the level of low density LDL cholesterol, as assessed after receiving the first CNI, compared to a baseline level of LDL. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater increase in the level of low density LDL cholesterol, as assessed after receiving the first CNI, compared to a baseline level of LDL.

[0292] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15%, 20%, 25%, or 30% or greater decrease in the level of LDL, as assessed after receiving the voclosporin, compared to the level of LDL, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15% or greater decrease in the level of LDL, as assessed after receiving the voclosporin, compared to the level of LDL, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 20% or greater decrease in the level of LDL, as assessed after receiving the voclosporin, compared to the level of LDL, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 25% or greater decrease in the level of LDL, as assessed after receiving the voclosporin, compared to the level of LDL, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30% or greater decrease in the level of LDL, as assessed after receiving the voclosporin, compared to the level of LDL, as assessed after receiving the first CNI, but before receiving voclosporin.

[0293] In some of any embodiments, the lipid is total cholesterol, and the predetermined range is less than 170 mg / dL, or betweenl 00-200 mg / dL, or between 125 -200 mg / dL. In some of any embodiments, the lipid is total cholesterol, and the predetermined range is 100- 200 mg / dL. In some of any embodiments, the lipid is triglycerides, and the predetermined range is less than 150 mg / dL, or between 50-150 mg / dL. In some of any embodiments, the lipid is triglycerides, and the predetermined range is 50-150 mg / dL. In some of any embodiments, the lipid is LDL, and the predetermined range is less than 100, 110, 120, or 130 mg / dL or betweenl0-130, 30-130 or 50-130 mg / dL. In some of any embodiments, the lipid is LDL, and the predetermined range is 50-130 mg / dL. In some of any embodiments,the lipid is HDL, and the predetermined range is 40, 45 or 50 mg / dL or higher, or between 35-60 mg / dL. In some of any embodiments, the lipid is LDL, and the predetermined range is 35-60 mg / dL.G. Glucose Dysregulation

[0294] In some embodiments, provided methods disclosed herein include selecting a subject who exhibits one or more indicators of new-onset diabetes after previously receiving a first CNI for immunosuppression. In some embodiments, the one or more indicators of new-onset diabetes is assessed based on any known methods to assess or diagnose diabetes, including assessments related to insulin signaling, glucose metabolism or regulation.

[0295] In some embodiments, the selected subject is administered voclosporin. In some embodiments, the new-onset diabetes is new-onset diabetes after transplant (NODAT).

[0296] In some embodiments, the one or more indicators of new-onset diabetes comprises total insulin secretion or islet cell death, or any assessments or indicators associated with or indicative of total insulin secretion or islet cell death. In some embodiments, the subject selected for administration of voclosporin exhibits inhibited total insulin secretion. In some embodiments, the subject selected for administration of voclosporin exhibits islet cell death.

[0297] In some embodiments, the one or more indicators of new-onset diabetes comprises assessing direct and indirect regulators of exocytosis, or any assessments or indicators associated with or indicative of assessing direct and indirect regulators of exocytosis. In some embodiments, the methods and uses involve assessing direct and indirect regulators of exocytosis compared to a baseline level, and if inhibition of the regulators are observed, selecting the subject for voclosporin administration.

[0298] In some embodiments, the regulator is SYT16. In some embodiments, the regulator is TBC1D30. In some embodiments, the regulator is PCK1. In some embodiments, the regulator is SMOC1. In some embodiments, the regulator is SYT5. In some embodiments, the regulator is PDK4. In some embodiments, the regulator is CREM.

[0299] In some embodiments, the subject is selected if the subject has increased susceptibility to new-onset diabetes after receiving the first CNI. In some embodiments, the subject is selected if the subject has increased susceptibility to new-onset diabetes compared to a corresponding population of individuals. In some embodiments, the population of individuals refers to a diseased general population. In some embodiments, the population ofindividuals refers to general population of a specific gender. In some embodiments, the population of individuals refers to general population of a specific race. In some embodiments, the population of individuals refers to general population of a specific age group. In some embodiments, the population of individuals refers to general population of a specific geographical region. In some aspects, the provided embodiments include assessing or monitoring the risk of new-onset diabetes, for example, by assessing or measuring one or more of the indicators described herein, or changes of the one or more of the indicators described herein.H. Biomarkers

[0300] In some embodiments, biomarkers can be used to identify subjects who may be experiencing kidney injury, inflammation, and fibrosis. In some embodiments, the one or more indicators of drug-induced nephrotoxicity comprises an increase in biomarkers associated with kidney injury, inflammation, and fibrosis, or any assessments or indicators associated with or indicative of an increase in biomarkers associated with kidney injury, inflammation, and fibrosis. In some embodiments, the methods and uses involve assessing the level of one or more urinary kidney injury and pro-fibrotic biomarkers of the subject compared to a baseline level such as cyclosporin, tacrolimus, or derivatives thereof, and if level of one or more urinary kidney injury and pro-fibrotic biomarkers is outside of a predetermined range, selecting the subject for voclosporin administration.

[0301] In some embodiments, the one or more biomarkers comprise kidney injury molecule-1 (KIM-1). In some embodiments, the one or more biomarkers comprise neutrophil gelatinase-associated lipocalin (NGAL). In some embodiments, the one or more biomarkers comprise monocyte chemoattractant protein-1 (MCP-1). In some embodiments, the one or more biomarkers comprise transforming growth factor beta (TGF-f> I ). In some embodiments, the one or more biomarkers comprise cluster of differentiation 163 (CD 163). In some embodiments, the one or more biomarkers comprise cluster of differentiation 206 (CD206). In some embodiments, the one or more biomarkers comprise interleukin- 16 (IL- 16).

[0302] In some embodiments, the subject selected for administration of voclosporin exhibits a 15%, 20%, 25% or 30% or greater increase in the level of kidney injury molecule-1 (KIM-1), as assessed after receiving the first CNI, compared to a baseline level of KIM-1. In some embodiments, the subject selected for administration of voclosporin exhibits a 15% orgreater increase in the level of kidney injury molecule-1 (KIM-1), as assessed after receiving the first CNI, compared to a baseline level of KIM-1. In some embodiments, the subject selected for administration of voclosporin exhibits a 20% or greater increase in the level of KIM-1, as assessed after receiving the first CNI, compared to a baseline level of KIM-1. In some embodiments, the subject selected for administration of voclosporin exhibits a 25% or greater increase in the level of KIM- 1, as assessed after receiving the first CNI, compared to a baseline level of KIM- 1. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater increase in the level of KIM-1, as assessed after receiving the first CNI, compared to a baseline level of KIM- 1.

[0303] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15%, 20%, 25%, or 30% or greater decrease in the level of KIM-1, as assessed after receiving the voclosporin, compared to the level of KIM-1, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15% or greater decrease in the level of KIM-1, as assessed after receiving the voclosporin, compared to the level of KIM-1, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 20% or greater decrease in the level of KIM- 1, as assessed after receiving the voclosporin, compared to the level of KIM-1, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 25% or greater decrease in the level of KIM-1, as assessed after receiving the voclosporin, compared to the level of KIM-1, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30% or greater decrease in the level of KIM- 1, as assessed after receiving the voclosporin, compared to the level of KIM-1, as assessed after receiving the first CNI, but before receiving voclosporin.

[0304] In some embodiments, the subject selected for administration of voclosporin exhibits a 15%, 20%, 25%, or 30% or greater increase in the level of neutrophil gelatinase- associated lipocalin (NGAL), as assessed after receiving the first CNI, compared to a baseline level of NGAL. In some embodiments, the subject selected for administration of voclosporin exhibits a 15% or greater increase in the level of neutrophil gelatinase-associated lipocalin(NGAL), as assessed after receiving the first CNI, compared to a baseline level of NGAL. In some embodiments, the subject selected for administration of voclosporin exhibits a 20% or greater increase in the level of NGAL, as assessed after receiving the first CNI, compared to a baseline level of NGAL. In some embodiments, the subject selected for administration of voclosporin exhibits a 25% or greater increase in the level of NGAL, as assessed after receiving the first CNI, compared to a baseline level of NGAL. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater increase in the level of NGAL, as assessed after receiving the first CNI, compared to a baseline level of NGAL.

[0305] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15%, 20%, 25%, or 30% or greater decrease in the level of NGAL, as assessed after receiving the voclosporin, compared to the level of NGAL, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15% or greater decrease in the level of NGAL, as assessed after receiving the voclosporin, compared to the level of NGAL, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 20% or greater decrease in the level of NGAL, as assessed after receiving the voclosporin, compared to the level of NGAL, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 25% or greater decrease in the level of NGAL, as assessed after receiving the voclosporin, compared to the level of NGAL, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30% or greater decrease in the level of NGAL, as assessed after receiving the voclosporin, compared to the level of NGAL, as assessed after receiving the first CNI, but before receiving voclosporin.

[0306] In some embodiments, the subject selected for administration of voclosporin exhibits a 15%, 20%, 25%, of 30% or greater increase in the level of monocyte chemoattractant protein-1 (MCP-1), as assessed after receiving the first CNI, compared to a baseline level of MCP-1. In some embodiments, the subject selected for administration of voclosporin exhibits a 15% or greater increase in the level of monocyte chemoattractantprotein-1 (MCP-1), as assessed after receiving the first CNI, compared to a baseline level of MCP-1. In some embodiments, the subject selected for administration of voclosporin exhibits a 20% or greater increase in the level of MCP-1, as assessed after receiving the first CNI, compared to a baseline level of MCP-1. In some embodiments, the subject selected for administration of voclosporin exhibits a 25% or greater increase in the level of MCP-1, as assessed after receiving the first CNI, compared to a baseline level of MCP-1. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater increase in the level of MCP-1, as assessed after receiving the first CNI, compared to a baseline level of MCP-1.

[0307] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15%, 20%, 25%, or 30% or greater decrease in the level of MCP-1, as assessed after receiving the voclosporin, compared to the level of MCP-1, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15% or greater decrease in the level of MCP-1, as assessed after receiving the voclosporin, compared to the level of MCP-1, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 20% or greater decrease in the level of MCP-1, as assessed after receiving the voclosporin, compared to the level of MCP-1, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 25% or greater decrease in the level of MCP-1, as assessed after receiving the voclosporin, compared to the level of MCP-1, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30% or greater decrease in the level of MCP-1, as assessed after receiving the voclosporin, compared to the level of MCP-1, as assessed after receiving the first CNI, but before receiving voclosporin.

[0308] In some embodiments, the subject selected for administration of voclosporin exhibits a 15%, 20%, 25%, or 30% or greater increase in the level of transforming growth factor beta (TGF- 1), as assessed after receiving the first CNI, compared to a baseline level of TGF-pi. In some embodiments, the subject selected for administration of voclosporin exhibits a 15% or greater increase in the level of transforming growth factor beta (TGF- 1),as assessed after receiving the first CNI, compared to a baseline level of TGF- 1. In some embodiments, the subject selected for administration of voclosporin exhibits a 20% or greater increase in the level of TGF- 1), as assessed after receiving the first CNI, compared to a baseline level of TGF- 1. In some embodiments, the subject selected for administration of voclosporin exhibits a 25% or greater increase in the level of TGF- 1, as assessed after receiving the first CNI, compared to a baseline level of TGF- 1. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater increase in the level of TGF-pi, as assessed after receiving the first CNI, compared to a baseline level of TGF-pi.

[0309] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15%, 20%, 25%, or 30% or greater decrease in the level of TGF-B1, as assessed after receiving the voclosporin, compared to the level of TGF-B1, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15% or greater decrease in the level of TGF-B1, as assessed after receiving the voclosporin, compared to the level of TGF-B1, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 20% or greater decrease in the level of TGF-B1, as assessed after receiving the voclosporin, compared to the level of TGF-B1, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 25% or greater decrease in the level of TGF-B1, as assessed after receiving the voclosporin, compared to the level of TGF-B1, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30% or greater decrease in the level of TGF-B1, as assessed after receiving the voclosporin, compared to the level of TGF-B1, as assessed after receiving the first CNI, but before receiving voclosporin.

[0310] In some embodiments, the subject selected for administration of voclosporin exhibits a 15%, 20%, 25%, or 30% or greater increase in the level of cluster of differentiation 163 (CD 163), as assessed after receiving the first CNI, compared to a baseline level of CD 163. In some embodiments, the subject selected for administration of voclosporin exhibits a 15% or greater increase in the level of cluster of differentiation 163 (CD 163), asassessed after receiving the first CNI, compared to a baseline level of CD 163. In some embodiments, the subject selected for administration of voclosporin exhibits a 20% or greater increase in the level of CD163, as assessed after receiving the first CNI, compared to a baseline level of CD 163. In some embodiments, the subject selected for administration of voclosporin exhibits a 25% or greater increase in the level of CD 163, as assessed after receiving the first CNI, compared to a baseline level of CD 163. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater increase in the level of CD163, as assessed after receiving the first CNI, compared to a baseline level of CD163.

[0311] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15%, 20%, 25%, or 30% or greater decrease in the level of CD 163, as assessed after receiving the voclosporin, compared to the level of CD 163, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15% or greater decrease in the level of CD163, as assessed after receiving the voclosporin, compared to the level of CD163, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 20% or greater decrease in the level of CD163, as assessed after receiving the voclosporin, compared to the level of CD163, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 25% or greater decrease in the level of CD163, as assessed after receiving the voclosporin, compared to the level of CD163, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30% or greater decrease in the level of CD163, as assessed after receiving the voclosporin, compared to the level of CD163, as assessed after receiving the first CNI, but before receiving voclosporin.

[0312] In some embodiments, the subject selected for administration of voclosporin exhibits a 15%, 20%, 25%, or 30% or greater increase in the level of cluster of differentiation 206 (CD206), as assessed after receiving the first CNI, compared to a baseline level of CD206. In some embodiments, the subject selected for administration of voclosporin exhibits a 15% or greater increase in the level of cluster of differentiation 206 (CD206), asassessed after receiving the first CNI, compared to a baseline level of CD206. In some embodiments, the subject selected for administration of voclosporin exhibits a 20% or greater increase in the level of CD206, as assessed after receiving the first CNI, compared to a baseline level of CD206. In some embodiments, the subject selected for administration of voclosporin exhibits a 25% or greater increase in the level of CD206, as assessed after receiving the first CNI, compared to a baseline level of CD206. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater increase in the level of CD206, as assessed after receiving the first CNI, compared to a baseline level of CD206.

[0313] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15%, 20%, 25%, or 30% or greater decrease in the level of CD206, as assessed after receiving the voclosporin, compared to the level of CD206, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15% or greater decrease in the level of CD206, as assessed after receiving the voclosporin, compared to the level of CD206, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 20% or greater decrease in the level of CD206, as assessed after receiving the voclosporin, compared to the level of CD206, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 25% or greater decrease in the level of CD206, as assessed after receiving the voclosporin, compared to the level of CD206, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30% or greater decrease in the level of CD206, as assessed after receiving the voclosporin, compared to the level of CD206, as assessed after receiving the first CNI, but before receiving voclosporin.

[0314] In some embodiments, the subject selected for administration of voclosporin exhibits a 15%, 20%, 25%, or 30% or greater increase in the level of Interleukin- 16 (IL-16), as assessed after receiving the first CNI, compared to a baseline level of IL-16. In some embodiments, the subject selected for administration of voclosporin exhibits a 15% or greater increase in the level of Interleukin- 16 (IL-16), as assessed after receiving the first CNI,compared to a baseline level of IL-16. In some embodiments, the subject selected for administration of voclosporin exhibits a 20% or greater increase in the level of IL-16, as assessed after receiving the first CNI, compared to a baseline level of IL-16. In some embodiments, the subject selected for administration of voclosporin exhibits a 25% or greater increase in the level of IL- 16, as assessed after receiving the first CNI, compared to a baseline level of IL-16. In some embodiments, the subject selected for administration of voclosporin exhibits a 30% or greater increase in the level of IL-16, as assessed after receiving the first CNI, compared to a baseline level of IL-16.

[0315] In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15%, 20%, 25%, or 30% or greater decrease in the level of IL-16, as assessed after receiving the voclosporin, compared to the level of IL-16, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 15% or greater decrease in the level of IL-16, as assessed after receiving the voclosporin, compared to the level of IL-16, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 20% or greater decrease in the level of IL-16, as assessed after receiving the voclosporin, compared to the level of IL-16, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 25% or greater decrease in the level of IL-16, as assessed after receiving the voclosporin, compared to the level of IL-16, as assessed after receiving the first CNI, but before receiving voclosporin. In some embodiments, the subject selected for administration of voclosporin, after receiving the voclosporin, exhibits a 30% or greater decrease in the level of IL-16, as assessed after receiving the voclosporin, compared to the level of IL-16, as assessed after receiving the first CNI, but before receiving voclosporin.

[0316] In some embodiments, the subject is selected if the subject exhibits one or more of: (a) variability in P -glycoprotein expression and / or activity; (b) variability in CYP3A4 / 5 expression and / or activity, (c) older kidney age; (d) salt depletion; (e) the use of nonsteroidal anti-inflammatory drugs; and / or (f) genetic polymorphisms in TGF- and / or ACE gene. In some embodiments, the subject exhibits upregulation of local renal P-gly coprotein. In some embodiments, the subject exhibits about any one of 20%, 40%, 50%, 75%, 100%, 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 75-fold, 100-fold, 500-fold, 1000-fold or more upregulation of local renal P-gly coprotein compared to a corresponding population described above. In some embodiments, the subject exhibits one or more single nucleotide polymorphisms mABCBl gene. In some embodiments, the subject exhibits the TT genotype at position 3435 of the ABCB1 gene. In some embodiments, the subject exhibits the TT genotype at position 3435 of the ABCB1 gene in a grafted kidney. In some embodiments, the subject does not exhibit the TT genotype at position 2677 of the ABCB1 gene. In some embodiments, the subject does not exhibit the TT genotype at position 2677 of the ABCB1 gene in a grafted kidney. In some embodiments, the subject is selected if the subject has been exposed to or has been administered nonsteroidal anti-inflammatory drugs. In some embodiments, the subject exhibits an older kidney age, such as about any one of 1, 2, 3, 4, 5, 8, 10, 12, 15, 18, 20, 25, 30, 35, 40 older kidney age than a corresponding population described above. In some embodiments, the subject exhibits salt depletion, such as up to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80% or more depletion as compared to a corresponding population described above. In some embodiments, the subject exhibits salt depletion as a result of dietary sodium restriction. In some embodiments, salt depletion in the subject results in increased renal tubular reabsorption of drugs, such as about any one of 20%, 40%, 50%, 75%, 100%, 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 75-fold, 100-fold, 500-fold, 1000-fold or more drug reabsorption of drugs as compared to a corresponding population described above. In some embodiments, the subject exhibits one or more polymorphisms in CYP3A4 and / or CYP3A5 gene. In some embodiments, the subject is a CYP3A5*! carrier. In some embodiments, the hepatic and intestinal CYP3A5 of the subject are expressed from CYP3A5*1. In some embodiments, the subject is a CYP3A5*! carrier, and generation of tacrolimus metabolite in the subject liver is any one of 20%, 40%, 50%, 75%, 100%, 2-fold, 5 -fold, 10-fold, 20-fold, 50-fold, 75-fold, 100-fold, 500-fold, 1000-fold or higher than that of a corresponding population described above. In some embodiments, the subject exhibits genetic polymorphisms in TGF- and / or Angiotensin converting enzyme (ACE). In some embodiments, the subject is selected if the subject has increased ACE activity, such as about any one of 20%, 40%, 50%, 75%, 100%, 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 75-fold, 100-fold, 500-fold, 1000-fold or more increased activity. In some embodiments, the subject is selected if the subject has increased serum levels of ACE, such as about any one of 20%, 40%, 50%, 75%, 100%, 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 75-fold, 100-fold, 500-fold, 1000-fold or more increased serum ACE levels. In some embodiments, the subject exhibitsTGF-P polymorphism in codon 10. In some embodiments, the subject exhibits increased local TGF-P production in allograft. In some embodiments, the subject is selected if the subject has upregulation of TGF-P in tubular epithelial cells, such as about any one of TGF-P 20%, 40%, 50%, 75%, 100%, 2-fold, 5-fold, 10-fold, 20-fold, 50-fold, 75-fold, 100-fold, 500- fold, 1000-fold or more upregulation of TGF-P in tubular epithelial cells.I. Hepatic Function

[0317] In some embodiments, the subject is selected if the subject exhibits hepatic impairment after receiving the first CNI. In some embodiments, the subject exhibits mild hepatic impairment (Child-PughA) or moderate hepatic impairment (Child-PughB). In some embodiments, the voclosporin Cmax and / or AUC are increased in subjects with hepatic impairment compared to corresponding subjects without such impairments. In some embodiments, the voclosporin Cmaxis increased by about any one of 1.1 -fold, 1.2-fold, 1.3- fold, 1.4-fold, 1.5-fold, 1.6-fold, 1.7-fold, 1.8-fold, 1.9-fold, 2.0-fold, 3.0-fold, 5.0-fold, 10.0- fold or more in subjects with mild or moderate hepatic impairment compared to corresponding subjects without such impairments. In some embodiments, the voclosporin AUC is increased by about any one of 1.1-fold, 1.2-fold, 1.4-fold, 1.6-fold, 1.8-fold, 2.0-fold, 2.2-fold, 2.4-fold, 2.6-fold, 2.8-fold, 3.0-fold, 4.0-fold, 5.0-fold, 10.0-fold or more in subjects with mild moderate renal impairment compared to corresponding subjects without such impairments.III. ADMINISTRATION OF VOCLOSPORIN

[0318] In some embodiments, the subject is administered voclosporin after having previously received a first CNI (e.g., cyclosporin, tacrolimus, or a derivative thereof) for immunosuppression. In some aspects, voclosporin is administered to a subject selected in accordance with the criteria described herein. In some aspects, the administration of the first CNI is discontinued, and the subject is administered voclosporin. In some aspects, in accordance with the provided embodiments, the subject that is in need of CNI therapy, switches the CNI from a legacy CNI (e.g., cyclosporin, tacrolimus, or a derivative thereof) to voclosporin.

[0319] In some embodiments, voclosporin is administered at a dose and timing that follows a known, recommended, approved, or typical treatment regimen for voclosporin. In some aspects, exemplary dosages, timing and treatment regimen for voclosporin aredescribed herein. In some aspects, dosages, timing and treatment regimen for voclosporin can be adjusted based on changes in recommendations or approved treatment regimen.A. Compositions

[0320] In some aspects, compositions comprising voclosporin is employed in the provided methods and uses. In some embodiments, a subject to be treated in accordance with the provided embodiments is a subject that is in need of immunosuppression, such as intermittent, long-term or even life-long immunosuppression, for example, using CNIs such as voclosporin or a pharmaceutically acceptable salt thereof. In some aspects, voclosporin, a therapeutically effective amount thereof, and / or a composition comprising voclosporin or a pharmaceutically acceptable salt thereof, is employed in the provided compositions, methods and uses. Uses include uses of voclosporin or composition comprising the same, in such methods, such as therapeutic or prophylactic methods, and treatments, such as a treatment regimen, and uses of voclosporin, a pharmaceutically acceptable salt thereof, or composition comprising the same, in the preparation of a medicament, in order to carry out such therapeutic or prophylactic methods and treatments.

[0321] Voclosporin (VCS), described in US Patent No. 9,765,119, hereby incorporated by reference in its entirety, represents a superior CNI, due to its reduced toxicity and ability to be variably dosed to maximize subject tolerance and efficacy. In some aspects, voclosporin is administered to a subject in need of therapy with a CNI, in combination with additional therapeutic agents, including background immunosuppressive therapy. In some aspects, voclosporin exhibits a linear pharmacokinetic profile resulting in a consistent doseconcentration relationship. In some aspects, voclosporin provides an advantage of eliminating the need for therapeutic drug monitoring typically associated with use of CNI. In some embodiments, voclosporin provides a predictable pharmacokinetic profile resulting in no need for the therapeutic drug monitoring required of other CNIs.

[0322] Voclosporin has a modification of a functional group on the amino acid-1 residue of the molecule compared to cyclosporine A (CsA), which enhances its binding to calcineurin, and confers better metabolic stability. Voclosporin has been studied in psoriasis, renal organ transplantation, and was recently FDA-approved for treatment of active lupus nephritis (LN) in combination with background immunosuppressive therapy. Observations show that VCS is more potent and less toxic at therapeutic levels than other immunosuppressants in its class.

[0323] VCS has shown to inhibit norovirus replication in a CypA-dependent manner and more effectively than CsA. This alteration has changed the binding of voclosporin to calcineurin and has been shown both in vitro and in vivo to increase the binding affinity up to five-fold compared to CsA (Kuglstatter et al., Acta Cryst. 2011; D67 : 119-23). This modification has also changed the metabolic profile of voclosporin by shifting metabolism away from amino acid-1, which is the major site of metabolism for CsA. The altered metabolic profile has led to a faster elimination of metabolites resulting in lower metabolite exposure compared to CsA. The combination of increased potency and decreased metabolite exposure for voclosporin compared to CsA, has led to better PK / PD relationship, administration of lower doses, and a potentially improved safety profile compared to CsA.

[0324] Voclosporin is a cyclosporine analogue modified at the 1 -amino acid residue with a 1,3-diene substituent. Voclosporin may exist as an isomeric mixture of Z- and E- isomers, and in some embodiments may be a mixture comprising at least about 90% (e.g., about 90% to about 95%) of the E-isomer and no more than about 10% (e.g., about 10% to about 5%) of the Z-isomer. In some aspects, the voclosporin composition comprises an isomeric mixture of voclosporin a pharmaceutically acceptable salt thereof, wherein the isomeric mixture comprises about 90% to about 95% of the E-isomer and about 10% to about 5% of the Z- isomer. In some aspects, the voclosporin composition comprises an isomeric mixture of voclosporin a pharmaceutically acceptable salt thereof, wherein the isomeric mixture comprises about 90% to about 95% of the E-isomer and about 10% to about 5% of the Z- isomer. Voclosporin has the structure shown below and is disclosed in U.S. Patent No. 7,332,472, which is incorporated herein by reference in its entirety.

[0325] Voclosporin may be referred to as cyclo {{(6E)-(2S,3R,4R)-3-hydroxy-4-methyl-2-(methylamino)-6,8-nonadienoyl}-L-2-aminobutyryl-N-methyl-glycyl-N-methyl-L-leucyl- L-valyl-N-methyl-L-leucyl-L-alanyl-D-alanyl-N-methyl-L-leucyl-N-methyl-L-leucyl-N- methyl-L-valyl}, (3S,6S,9S,12R,15S,18S,21S,24S,30S, 33S)-30-ethyl-33-((lR,2R,E)-l- hydroxy-2-methylhepta-4,6-dien-l-yl)-6,9,18,24-tetraisobutyl-3,21-diisopropyl- l,4,7,10,12,15,19,25,28-nonamethyl-l,4,7,10,13,16,19,22,25,28,31- undecaazacyclotritriacontan-2,5,8,ll,14,17,20,23,26,29,32-undecaone, or (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(lR,2R,4E)-l-hydroxy-2- methylhepta-4,6-dienyl]-l,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2- methylpropyl)-3.21 -di(propan-2-y 1)- 1 ,4,7, 10, 13 , 16, 19,22,25 ,28,31 - undecazacyclotritriacontane-2,5,8,ll,14,17,20,23,26,29,32-undecone. Voclosporin is also known as LUPKYNIS®, ISATX247, ISA247, LX211, or Luveniq. In some aspects, reference to voclosporin and administration of voclosporin also can include a pharmaceutically acceptable salt of voclosporin, and administration of a pharmaceutically acceptable salt of voclosporin. In some aspects, a “pharmaceutically acceptable salt” refers to a salt of any of the compounds (e.g., voclosporin) which are known to be non-toxic and are commonly used in the pharmaceutical literature. In some embodiments, the pharmaceutically acceptable salt of voclosporin retains the biological effectiveness of voclosporin and are not biologically or otherwise undesirable.

[0326] Voclosporin has an empirical formula of C63H111N11O12 and a molecular weight of 1214.6 g / mole. At ambient temperature, voclosporin is freely soluble in acetone, acetonitrile, ethanol, and methanol, and practically insoluble in heptanes (USP). Voclosporin is practically insoluble (less than 0.1 g / L at 20°C) in water and melts above 144°C with decomposition.

[0327] In some embodiments of the methods and uses provided herein, the method or the treatment comprises administering voclosporin or a pharmaceutically acceptable salt thereof with a therapeutically effective amount of MMF and / or a therapeutically effective amount of a corticosteroid. In some embodiments, the method treatment comprises administering voclosporin or a pharmaceutically acceptable salt thereof without a therapeutically effective amount of MMF and / or a therapeutically effective amount of a corticosteroid.

[0328] In some embodiments, the methods and uses involve administering a composition, such as a pharmaceutical composition or a therapeutic composition, comprising voclosporin. In some embodiments, the methods and uses involve administering a composition comprisingvoclosporin.

[0329] In some embodiments, the composition comprising voclosporin comprises an isomeric mixture of voclosporin E-isomer and Z-isomer. Mixtures of the E and Z isomers of voclosporin are described in U.S. Patent 6,998,385. Mixtures with a preponderance of the E- isomer are described in U.S. Patent 7,332,472 describing exemplary indications that can be treated with the isomeric voclosporin mixture including glomerulonephritis. Various formulations of voclosporin mixtures are also described in U.S. Patent Nos. 7,060,672;7,429,562 and 7,829,533. In some embodiments, the isomeric mixture comprises at least about 99%, about 98%, about 97%, about 96%, about 95%, about 94%, about 93%, about 92%, about 91%, about 90%, about 80%, about 70%, about 60%, about 50%, about 40%, about 30%, about 20%, or about 10% of voclosporin E-isomer by weight. In some embodiments, the isomeric mixture comprises at least 90% of voclosporin E-isomer by weight. In some embodiments, the isomeric mixture comprises at least 95% of voclosporin E-isomer by weight.

[0330] In some embodiments, the pharmaceutical compositions (e.g., comprising voclosporin) is or comprises a pharmaceutical formulation. In some embodiments, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, buffers, carriers and / or vehicles. In some embodiments, the pharmaceutical composition contains pharmaceutical carriers and excipients appropriate for the type of administration contemplated.

[0331] In some aspects, generally, the pharmaceutically acceptable carriers or vehicles, such as those present in the pharmaceutically acceptable buffer, can be any known in the art. Remington’s Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, Pa., 19thEdition (1995), describes compositions and formulations suitable for pharmaceutical delivery of one or more therapeutic compounds. Pharmaceutically acceptable compositions generally are prepared in view of approvals for a regulatory agency or other agency prepared in accordance with generally recognized pharmacopeia for use in animals and in humans.

[0332] Pharmaceutical compositions can include carriers such as a diluent, adjuvant, excipient, or vehicle with which the compound is administered. Examples of suitable pharmaceutical carriers are described in “Remington’s Pharmaceutical Sciences” by E. W. Martin. Such compositions will contain a therapeutically effective amount of the compound, generally in purified form, together with a suitable amount of carrier so as to provide theform for proper administration to the patient. Such pharmaceutical carriers can be sterile liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin. Water is a typical carrier when the pharmaceutical composition is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions also can be employed as liquid carriers, particularly for injectable solutions. A composition, if desired, also can contain minor amounts of wetting or emulsifying agents, or pH buffering agents. Typically, the compositions containing the compounds are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see e.g., Ansel Introduction to Pharmaceutical Dosage Forms, Fourth Edition, 1985, 126). Generally, the mode of formulation is a function of the route of administration. Exemplary formulations of voclosporin mixtures are also described in U.S. Patent Nos. 7,060,672; 7,429,562 and 7,829,533.B. Dose and Timing of Voclosporin Administration

[0333] In some aspects, voclosporin is administered in a predetermined daily dosage of 39.5 mg BID, 31.6 mg BID, 23.7 mg BID, 15.8 mg BID, of 7.9 mg BID. In some aspects, the predetermined daily dosage is any one of about 7.9 to 23.7, 23.7 to 31.6, 31.6 to 39.5, or 39.5 to 79 mg voclosporin. In some aspects, the predetermined daily dosage is about 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 60, 80, 100 mg voclosporin, or any values there between.

[0334] In some aspects, the first time point is any one of about 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 24, 36, or 48 hours preceding initiating the voclosporin treatment. In some aspects, the first time point is immediately preceding initiating the voclosporin treatment. In some aspects, the second time point is any one of about 1, 2, 3, 4, 5, 10, 14, 15, 20, 25, 28, 30, 40, 50 or more days subsequent to initiating the voclosporin treatment, or any time periods there between. In some aspects, the second time point is any one of about 1, 2, 3, 4, 5, 8 10, 12, 15, 16, 20, 24, 25, 28, 30, 32, 35, 36, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120, 150 or more weeks subsequent to initiating the voclosporin treatment, or any time periods there between.

[0335] In some aspects, the predetermined daily dosage of effective amounts of voclosporin is about any one of 5, 7.9, 10, 12, 15, 15.8, 20, 23.7, 25, 28, 30, 31.6, 35, 39.5, 40, 45, 50 mg BID, or any amounts there between. In some aspects, the predetermined daily dosage of voclosporin is 39.5 mg BID, 31.6 mg BID, 23.7 mg BID, 15.8 mg BID, or 7.9 mgBID.

[0336] In some aspects, the subject has severe renal impairment at baseline, the predetermined daily dosage of effective amounts of voclosporin is about any one of 2, 5, 7.9, 10, 12, 15, 15.8, 20, 23.7, 25, 28, 30, 31.6, 35 mg BID, or any amounts there between. In some aspects, the subject has severe renal impairment at baseline, the predetermined daily dosage of effective amounts of voclosporin is about 15.8 mg BID.

[0337] In some aspects, the subject has moderate hepatic impairment, the predetermined daily dosage of effective amounts of voclosporin is about any one of 2, 5, 7.9, 10, 12, 15, 15.8, 20, 23.7, 25, 28, 30, 31.6, 35 mg BID, or any amounts there between. In some aspects, the subject has moderate hepatic impairment, the predetermined daily dosage of effective amounts of voclosporin is about 15.8 mg BID.

[0338] In some aspects, voclosporin is administered long-term. In some aspects, voclosporin is administered in one or more doses. In some aspects, voclosporin administration comprises an initial dose (or a first dose) and one or more subsequent doses.

[0339] In some aspects of the methods and uses provided herein, voclosporin is administered four times a day, three time a day, twice a day (BID), or once a day. In some aspects, voclosporin is administered four times a day. In some aspects, voclosporin is administered three times a day. In some aspects, voclosporin is administered twice a day (BID). In some aspects, voclosporin is administered once a day.

[0340] In some aspects, voclosporin is administered at a constant dose throughout the voclosporin treatment period. In some aspects, the dosage of voclosporin can vary during the voclosporin treatment period, for example, based on the assessment of therapy.

[0341] In some aspects, daily dosage of voclosporin is about 1 mg to about 250 mg, about 5 mg to about 250 mg, about 10 mg to about 250 mg, about 50 mg to about 250 mg, about 100 mg to about 250 mg, about 150 mg to about 250 mg, about 200 mg to about 250 mg, 1 mg to about 200 mg, about 5 mg to about 200 mg, about 10 mg to about 200 mg, about 50 mg to about 200 mg, about 100 mg to about 200 mg, about 150 mg to about 200 mg, about 1 mg to about 150 mg, about 5 mg to about 150 mg, about 10 mg to about 150 mg, about 50 mg to about 150 mg, about 100 mg to about 150 mg, about 1 mg to about 100 mg, about 5 mg to about 100 mg, about 10 mg to about 100 mg, about 50 mg to about 100 mg, about 1 mg to about 50 mg, about 5 mg to about 50 mg, or about 10 mg to about 50 mg. In someaspects, daily dosage of voclosporin is about 1 mg, about 5 mg, about 10 mg, about 20 mg, about 30 mg, about 40 mg, about 50 mg, about 60 mg, about 70 mg, about 80 mg, about 90 mg, about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, or about 250 mg. In some aspects, daily dosage of voclosporin is at least about 1 mg, at least about 5 mg, at least about 10 mg, at least about 20 mg, at least about 30 mg, at least about 40 mg, at least about 50 mg, at least about 60 mg, at least about 70 mg, at least about 80 mg, at least about 90 mg, at least about 100 mg, at least about 110 mg, at least about 120 mg, at least about 130 mg, at least about 140 mg, at least about 150 mg, at least about 160 mg, at least about 170 mg, at least about 180 mg, at least about 190 mg, or at least about 200 mg.

[0342] In some aspects, dosage of voclosporin is about 0. 1 mg / kg / day to about 2 mg / kg / day, about 0.5 mg / kg / day to about 2 mg / kg / day, about 1 mg / kg / day to about 2 mg / kg / day, about 1.5 mg / kg / day to about 2 mg / kg / day, about 0.1 mg / kg / day to about 1.5 mg / kg / day, about 0.5 mg / kg / day to about 1.5 mg / kg / day, about 1 mg / kg / day to about 1.5 mg / kg / day, about 0.1 mg / kg / day to about 1.0 mg / kg / day, about 0.5 mg / kg / day to about 1.0 mg / kg / day, or about 0.1 mg / kg / day to about 0.5 mg / kg / day. In some aspects, dosage of voclosporin is about 0.1, about 0.2, about 0.3, about 0.4, about 0.5, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.1, about 1.2, about 1.3, about 1.4, about 1.5, about 1.6, about 1.7, about 1.8, about 1.9, or about 2.0 mg / kg / day. In some aspects, dosage of voclosporin is at least about 0.1, at least about 0.2, at least about 0.3, at least about 0.4, at least about 0.5, at least about 0.6, at least about 0.7, at least about 0.8, at least about 0.9, at least about 1.0, at least about 1.1, at least about 1.2, at least about 1.3, at least about 1.4, at least about 1.5, at least about 1.6, at least about 1.7, at least about 1.8, at least about 1.9, or at least about 2.0 mg / kg / day.

[0343] In some aspects, suitable dosages of voclosporin are in increment of about 7.9 mg. In some aspects, the dosage of voclosporin is about 7.9 mg QD, about 15.8 mg QD, about 23.7 mg QD, about 31.6 mg QD, about 39.5 mg QD, about 47.4 mg QD, about 55.3 mg QD, about 63.2 mg QD, about 71.1 mg QD, about 79.0 mg QD, about 86.9 mg QD, about 94.8 mg QD, about 102.7 mg QD, or about 110.6 mg QD. In some aspects, the dosage of voclosporin is about 7.9 mg BID, about 15.8 mg BID, about 23.7 mg BID, about 31.6 mg BID, about 39.5 mg BID, about 47.4 mg BID, or about 55.3 mg BID. In some aspects, the dosage ofvoclosporin is about 7.9 mg BID. In some aspects, the dosage of voclosporin is about 15.8 mg BID.

[0344] In some aspects, suitable dosages of voclosporin are in increments of 7.9 mg including 39.5 mg, 31.6 mg, 23.7 mg, 15.8 mg or 7.9 mg. Low dosages show superior results compared to a higher dose of 39.5 mg each of such administrations carried out twice daily. Doses as low as 15.8 mg or 7.9 mg twice daily are effective. In some aspects, the dosage of voclosporin is about 23.7 mg BID.

[0345] The dosage indicated, for example 23.7 mg is subject to slight variations, typically ±10% or, alternatively, for 23.7 mg specified between 21 mg and 26 mg BID. This is due to inconsistencies in pharmaceutical manufacture and the ideal dosage is the specified dose — i.e., for example, 23.7 mg BID. Comparable variations applied to the alternative dosages, and to the differential adjustment.

[0346] In some aspects, the blood trough level is about 25 to about 60 ng / mL. In some aspects, the blood trough level is about 25, about 30, about 35, about 40, about 45, about 50, about 55, or about 60 ng / mL.

[0347] In some aspects, the therapeutically effective amount of voclosporin is an amount that is equivalent to can be extrapolated to, can achieve, or can achieve as a Cmax of a concentration of between about 0.05 pM and about 10 pM. about 0.1 pM and about 5 pM, about 0.2 pM and about 2.5 pM, about 0.3 pM and about 1.0 pM, about 0.4 pM and about 0.9 pM, about 0.5 pM and about 0.8 pM, about 0.1 pM and about 0.5 pM, or about 0.2 pM and about 0.4 pM. In some aspects, the therapeutically effective amount of voclosporin is an amount that is equivalent to, can be extrapolated to, can achieve, or can achieve as a Cmax of a concentration of about 0.05, about 0.1, about 0.15, about 0.2, about 0.25, about 0.3, about 0.35, about 0.4, about 0.45, about 0.5, about 0.55, about 0.6, about 0.7, about 0.8, about 0.9, about 1.0, about 1.5, about 2.0, about 2.5, about 3.0, about 3.5, about 4.0, about 4.5, about 5.0, about 6.0, about 7.0, about 8.0, about 9.0, or about 10.0 pM or less. In some aspects, the therapeutically effective amount of voclosporin is an amount that is equivalent to, can be extrapolated to, can achieve, or can achieve as a Cmax of a concentration of about 0.2 pM. In some aspects, the therapeutically effective amount of voclosporin is an amount that is equivalent to, can be extrapolated to, can achieve, or can achieve as a Cmax of a concentration of about 0.3 pM. In some aspects, the therapeutically effective amount of voclosporin is an amount that is equivalent to, can be extrapolated to, can achieve, or canachieve as a Cmax of a concentration of about 0.4 pM. In some aspects, the therapeutically effective amount of voclosporin is an amount that is equivalent to, can be extrapolated to, can achieve, or can achieve as a Cmax of a concentration of about 0.5 pM.

[0348] In some aspects, voclosporin is administered based on a treatment regimen over a voclosporin treatment period. In some aspects, the voclosporin treatment regimen further includes assessing the estimated Glomerular Filtration Rate (eGFR) of the subject at at least a first time point and a second time point on different days of voclosporin treatment period, and if the eGFR of the subject decreases by more than a target % to below a predetermined value, between said first and second time points, reducing the daily dosage by increment(s) of 7.9 mg BID or stopping the administering of voclosporin to the subject. In some examples, the voclosporin treatment regimen further includes assessing the estimated Glomerular Filtration Rate (eGFR) of the subject at at least a first time point and a second time point on different days of voclosporin treatment period, and if the eGFR of the subject decreases by less than said target %, between said first and second time points, the method includes continuing administering the same predetermined daily dosage of voclosporin to the subject.

[0349] In some aspects, the voclosporin treatment period is at least any one of about 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120 weeks, or 130 weeks, or any length of treatment periods there between. In particular embodiments, the voclosporin treatment period is at least about 65 weeks. In particular embodiments, the voclosporin treatment period is at least about 65 weeks. In some aspects, the first time point is immediately preceding initiating the voclosporin treatment. In some examples, the predetermined value is in the range of about 30 to about 110 ml / min / 1.73m2. In some aspects, the predetermined value is in the range of about 50 to about 90 ml / min / 1.73 m2In some aspects, the predetermined value is in the range of about any one of 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 80, 80 to 90, 90 to 100 and 100-110 ml / min / 1.73 m2In some aspects, the predetermined value is any one of about 30, 40, 50, 60, 70, 80, 90, or 100 ml / min / 1.73 m2In some aspects, the predetermined value is about 60 ml / min / 1.73 m2In some aspects, the target % is in the range of about 10% to about 60%. In some aspects, the target % is in the range of about 20% to about 45%. In some aspects, the target % is in the range of about any one of 10% to 20%, 20% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, 45% to 50%, 50% to 55% and 55% to 60%. In some aspects, the target % is approximately 20%. In some aspects, the target % is approximately 30%.

[0350] In some aspects, the voclosporin treatment regimen further includes assessing the estimated Glomerular Filtration Rate (eGFR) of the subject at at least a first time point and a second time point on different days of voclosporin treatment period, and if the eGFR of the subject decreases by more than a 20% to below 60 ml / min / 1.73 m2, between said first and second time points, reducing the daily dosage by increment(s) of 7.9 mg BID or stopping the administering of voclosporin to the subject. In some examples, the voclosporin treatment regimen further includes assessing the estimated Glomerular Filtration Rate (eGFR) of the subject at at least a first time point and a second time point on different days of voclosporin treatment period, and if the eGFR of the subject decreases by less than 20%, between said first and second time points, the method includes continuing administering the same predetermined daily dosage of voclosporin to the subject.

[0351] In some aspects, the treatment regimen comprises assessing the estimated Glomerular Filtration Rate (eGFR) of the subject at at least a first time point and a second time point on different days of voclosporin treatment period, the first time point is immediately preceding initiating the voclosporin treatment. In some embodiment, the treatment regimen further comprises assessing eGFR of the subject every two weeks subsequent to initiating the voclosporin treatment. In some aspects, the treatment regimen comprises assessing eGFR of the subject every two weeks in the first month, and every four weeks thereafter, subsequent to initiating the voclosporin treatment. In some aspects, eGFR of the subject decreases by more than a target % to below a predetermined value at any assessment subsequent to initiating the voclosporin treatment, the treatment regimen comprises reducing the daily dosage by increment(s) of 7.9 mg BID or stopping the administering of voclosporin to the subject.

[0352] In some aspects, the treatment regimen comprises assessing the eGFR of the subject at at least a first time point and a second time point on different days of voclosporin treatment period, the first time point is immediately preceding initiating the voclosporin treatment. In some aspects, eGFR of the subject decreases by more than a target % compared to eGFR at the first time point to below a predetermined value at an assessment subsequent to initiating the voclosporin treatment, the treatment regimen comprises reducing the daily dosage by 7.9 mg BID. In some aspects, eGFR of the subject decreases by more than the target % compared to eGFR at the first time point to below the predetermined value at an assessment subsequent to initiating the voclosporin treatment, and the daily dosage is reducedby 7.9 mg BID, the treatment regimen comprises assessing eGFR of the subject two weeks subsequent to dosage reduction, and further comprises a second reduction of daily dosage by 7.9 mg BID if eGFR of the subject decreases by more than the target % compared to eGFR at the first time point to the predetermined value in the assessment two weeks subsequent to the first dosage reduction. In some aspects, the treatment regimen comprises one or more dosage reductions, the treatment regimen comprises assessing eGFR of the subject every two weeks subsequent to the one or more dosage reductions, and comprises increasing the daily dosage by 7.9 mg BID for each eGFR assessment where eGFR of the subject decreases by less than the target % compared to eGFR at the first time point. In some aspects, the dosage increase does not cause the dosage to exceed the initial predetermined dosage. In some examples, the predetermined value is in the range of about 30 to about 110 ml / min / 1.73 m2In some aspects, the predetermined value is in the range of about 50 to about 90 ml / min / 1.73 m2In some aspects, the predetermined value is in the range of about any one of 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 80, 80 to 90, 90 to 100 and 100-110 ml / min / 1.73 m2In some aspects, the predetermined value is any one of about 30, 40, 50, 60, 70, 80, 90, or 100 ml / min / 1.73 m2In some aspects, the predetermined value is about 60 ml / min / 1.73 m2In some aspects, the target % is in the range of about 10% to about 60%. In some aspects, the target % is in the range of about 10% to about 45%. In some aspects, the target % is in the range of about any one of 10% to 20%, 20% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, 45% to 50%, 50% to 55% and 55% to 60%. In some aspects, the target % is approximately 20%.

[0353] In some aspects, eGFR of the subject decreases by between about 20% to about 30% compared to eGFR at the first time point to below 60 ml / min / 1.73 m2at an assessment subsequent to initiating the voclosporin treatment, the treatment regimen comprises reducing the daily dosage by 7.9 mg BID. In some aspects, eGFR of the subject decreases by between about 20% to about 30% compared to eGFR at the first time point, to below 60 ml / min / 1.73 m2at an assessment subsequent to initiating the voclosporin treatment, and the daily dosage is reduced by 7.9 mg BID, the treatment regimen comprises assessing eGFR of the subject two weeks subsequent to dosage reduction, and further comprises a second reduction of daily dosage by 7.9 mg BID if eGFR of the subject decreases by more than 20% compared to eGFR at the first time point to below 60 ml / min / 1.73 m2in the assessment two weeks subsequent to the first dosage reduction. In some aspects, the treatment regimen comprises one or more dosage reductions, the treatment regimen comprises assessing eGFR of thesubject every two weeks subsequent to the one or more dosage reductions, and comprises increasing the daily dosage by 7.9 mg BID for each eGFR assessment where eGFR of the subject decreases by less than 20% compared to eGFR at the first time point. In some aspects, the dosage increase does not cause the dosage to exceed the initial predetermined dosage.

[0354] In some aspects, the treatment regimen comprises assessing the eGFR of the subject at at least a first time point and a second time point on different days of voclosporin treatment period, the first time point is immediately preceding initiating the voclosporin treatment. In some aspects, eGFR of the subject decreases by equal to or more than a first target % compared to eGFR at the first time point to below a predetermined value at any assessment subsequent to initiating the voclosporin treatment, the treatment regimen comprises stopping the administering of voclosporin to the subject. In some aspects, eGFR of the subject decreases by equal or more than the target % compared to eGFR at the first time point to below the predetermined value at an assessment subsequent to initiating the voclosporin treatment, and the administration of voclosporin to the subject is stopped, the treatment regimen comprises assessing eGFR of the subject two weeks subsequent to stopping administration, and further comprises re-initiating the administration at the initial predetermined dosage if eGFR of the subject decreases by less than a second target % compared to eGFR at the first time point in the assessment two weeks subsequent to the stopping of administration of voclosporin. In some aspects, the predetermined value is in the range of about 50 to about 90 ml / min / 1.73m2. In some aspects, the predetermined value is in the range of about any one of 30 to 40, 40 to 50, 50 to 60, 60 to 70, 70 to 80, 80 to 90, 90 to 100 and 100-110 ml / min / 1.73m2. In some aspects, the predetermined value is any one of about 30, 40, 50, 60, 70, 80, 90, or 100 ml / min / 1.73 m2In some aspects, the predetermined value is about 60 ml / min / 1.73 m2In some aspects, the first target % is in the range of about 10% to about 60%. In some aspects, the first target % is in the range of about 20% to about 45%. In some aspects, the first target % is in the range of about any one of 10% to 20%, 20% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, 45% to 50%, 50% to 55% and 55% to 60%. In some aspects, the first target % is approximately 30%. In some aspects, the second target % is in the range of about 10% to about 60%. In some aspects, the second target % is in the range of about 10% to about 45%. In some aspects, the second target % is in the range of about any one of 10% to 20%, 20% to 30%, 30% to 35%, 35% to 40%, 40% to 45%, 45% to 50%, 50% to 55% and 55% to 60%. In some aspects, the second target % is approximately20%.

[0355] In some aspects, eGFR of the subject decreases by equal to or more than 30% compared to eGFR at the first time point to below 60 ml / min / 1.73 m2at any assessment subsequent to initiating the voclosporin treatment, the treatment regimen comprises stopping the administering of voclosporin to the subject. In some aspects, eGFR of the subject decreases by equal or more than 30% compared to eGFR at the first time point to below 60 ml / min / 1.73 m2at an assessment subsequent to initiating the voclosporin treatment, and the administration of voclosporin to the subject is stopped, the treatment regimen comprises assessing eGFR of the subject two weeks subsequent to stopping administration, and further comprises re-initiating the administration at the initial predetermined dosage if eGFR of the subject decreases by less than 20% compared to eGFR at the first time point in the assessment two weeks subsequent to the stopping of administration of voclosporin.

[0356] Exemplary treatment regimen for voclosporin include, measuring eGFR immediately prior to administering the first dose of voclosporin and at a second time point at least a day later and:(i) if the eGFR of the subject decreased by >_30% to a value of below 60 mL / min / 1.73m2between said first and second time points, stopping the administering of Voclosporin or reducing dosage thereof to the subject;(ii) if the eGFR of the subject decreased by between 20% to 30% to a value of below 60 ml / min / 1.73m2between said first and second time points, administering a reduced dosage of voclosporin to the subject; and(iii) if the eGFR of the subject decreased by <20% between said first and second time points, continuing administering the same predetermined daily dosage of voclosporin to the subject.

[0357] In some aspects, the voclosporin treatment regimen further includes identifying a subject as appropriate for the treatment regimen prior to conducting the treatment regimen on the subject by (a) determining that the urine protein creatinine ratio (UPCR) of the subject is > 1 mg / mg as measured by first morning void or 24 hour urine, and (b) determining that the subject has an eGFR as measured by Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EP1) of > 45 ml / min / 1.73 m2; if the conditions of (a) and (b) are met, the subject is identified as appropriate for the treatment regimen. In some aspects, the treatment regimen comprises determining that the urine protein creatinine ratio (UPCR) of the subjectis > 1.5 mg / mg as measured by first morning void or 24 hour urine.

[0358] In some aspects, one or more doses of voclosporin is administered to a subject. In some aspects, one or more doses of a legacy CNI as a first CNI, such as cyclosporin, tacrolimus or derivatives thereof, was previously administered to the subject. In some aspects, a first dose of the one or more doses of the voclosporin is administered later than a first dose of the one or more doses of the first CNI, such as such as cyclosporin, tacrolimus or derivatives thereof. In some aspects, the administration of the first CNI is discontinued, and the subject is administered voclosporin. In some aspects, the subject that is in need of CNI therapy, switches the CNI from a legacy CNI (e.g., cyclosporin, tacrolimus, or a derivative thereof) to voclosporin.

[0359] In some aspects, the projected voclosporin treatment period begins after a first CNI treatment period. In some aspects, the projected voclosporin treatment period begins after the end of the first CNI treatment period, or after discontinuing administration of the first CNI.

[0360] In some aspects, the projected voclosporin treatment period is between about 10 to 100 weeks, 10 to 90 weeks, 10 to 80 weeks, 10 to 70 weeks, 10 to 60 weeks, 10 to 50 weeks, 10 to 40 weeks, 10 to 30 weeks, or 10 to 20 weeks. In some aspects, the projected voclosporin treatment period is at least about 24 weeks, 36 weeks, 48 weeks, 52 weeks, 60 weeks, 72 weeks, 84 weeks or 96 weeks or longer. In some aspects, the projected voclosporin treatment period is at least about 24 weeks, In some aspects, the projected voclosporin treatment period is at least about 48 weeks, In some aspects, the projected voclosporin treatment period is at least about 52 weeks, In some aspects, the projected voclosporin treatment period is at least about 18 months, In some aspects, the projected voclosporin treatment period is at least about 24 months, In some aspects, the projected voclosporin treatment period is at least about 36 months, In some aspects, the projected voclosporin treatment period is at least about 48 months.C. Routes of Administration

[0361] In some embodiments of methods and uses disclosed herein, voclosporin may be administered in any suitable form and by any suitable route that will provide sufficient level of voclosporin such as by enteral administration (e.g., oral administration, sublingual administration, or rectal administration) or parenteral administration (e.g., intravenousinjection, intramuscular injection, subcutaneous injection, intravenous infusion, or inhalation / insufflation).

[0362] In some embodiments, voclosporin is administered by enteral administration. Exemplary routes of enteral administration include, without limitation, oral administration, sublingual administration, and rectal administration (e.g., through the rectum). In some embodiments, the enteral administration comprises oral administration. In some embodiments, the enteral administration comprises sublingual administration. In some embodiments, the enteral administration comprises rectal administration.

[0363] In some embodiments, voclosporin is administered by parenteral administration. Exemplary routes of parenteral administration include, without limitation, intravenous injection, intramuscular injection, subcutaneous injection, intravenous infusion, and inhalation / insufflation.

[0364] In some embodiments, voclosporin is administered by inhalation or insufflation. Exemplary types of preparations for inhalation and / or insufflation include, without limitation, sprays, aerosols, mists, capsules, powders, or cartridges for use in an inhaler or insufflator and solutions / suspensions for nebulization. In some embodiments, voclosporin is administered in the form of an aerosol, a spray, a mist, or a powder. In some embodiments, voclosporin is administered in the form of an aerosol. Examples of various types of devices for administering by inhalation or insufflation include, without limitation, a nebulizer, a metered dose inhaler (MDI), and a dry powder inhaler.D. Additional Therapeutic Agent

[0365] In some embodiments, the method or the treatment also involves administering a therapeutically effective amount of an additional therapeutic agent. In some embodiments, the method also comprises administering a therapeutically effective amount of an additional therapeutic agent. In some aspects, additional therapeutic agents include background immunosuppressive therapy, such as my cophenolate mofetil (MMF) or one or more corticosteroids.

[0366] In some embodiments, the method or use further includes administering to said subject an effective amount of my cophenolate mofetil (MMF). In some embodiments, the method or use further includes administering to said subject an effective amount of a corticosteroid.

[0367] In some embodiments, a dosage of MMF and a reducing dosage of corticosteroid is also administered in addition to voclosporin. In some aspects, exemplary doses of MMF includes 2 g daily; and exemplary doses of oral corticosteroids include daily dosages diminishing from 20-25 mg daily to 2.5 mg daily over a period of 16 weeks.

[0368] For example, with respect to corticosteroids, subjects who weigh 45kg or more may receive 0.5 g of methylprednisolone on days 1 and 2 of the study intravenously and then beginning on day 3, oral corticosteroid therapy. Subjects weighing <45 kg receive only half these dosages.

[0369] For oral prednisone, exemplary starting dosage for oral administration includes 20 mg / day for subjects < 45kg and 25 mg / day for subjects who weigh > 45kg. Exemplary dosing schedule for corticosteroids are set forth in Tables 2 and 3 below:Table 2: Standard of Care Dosing Schedule for IV methylprednisolone and daily oral prednisone:Table 3: Lowered Dosing Schedule for IV methylprednisolone and daily oral prednisone:

[0370] Voclosporin is a sensitive CYP3A4 substrate. Co-administration with strong or moderate CYP3A4 inhibitors increases voclosporin exposure. In some embodiments, the voclosporin Cmaxand / or AUC are increased in subjects receiving strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) or moderate CYP3A4 inhibitors (e.g.,verapamil, fluconazole, diltiazem) compared to corresponding subjects without receiving such CYP3A4 inhibitors. In some embodiments, the voclosporin Cmaxis increased by about any one of 1.1-fold, 1.2-fold, 1.4-fold, 1.6-fold, 1.8-fold, 2.0-fold, 2.2-fold, 2.4-fold, 2.6-fold, 2.8-fold, 3.0-fold, 4.0-fold, 5.0-fold, 10.0-fold or more in subjects receiving strong or moderate CYP3A4 inhibitors compared to corresponding subjects without receiving such CYP3A4 inhibitors. In some embodiments, the voclosporin AUC is increased by about any one of 2.0-fold, 2.2-fold, 2.4-fold, 2.6-fold, 2.8-fold, 3.0-fold, 3.0-fold, 3.2-fold, 3.4-fold, 3.6- fold, 3.8-fold, 4.0-fold, 5.0-fold, 10.0-fold or more in subjects receiving strong or moderate CYP3A4 inhibitors compared to corresponding subjects without receiving such CYP3A4 inhibitors.IV. DEFINITIONS

[0371] As used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural forms, unless the context clearly dictates otherwise.

[0372] As used herein, and unless otherwise specified, the terms “about” and “approximately,” when used in connection with doses or amounts, contemplate a dose or amount within 10%, within 5%, within 4%, within 3%, within 2%, within 1%, or within 0.5% of the specified dose or amount.

[0373] As used herein, “pharmaceutically acceptable” is meant a material that is not biologically or otherwise undesirable, e.g, the material may be incorporated into a pharmaceutical composition administered to a patient without causing any significant undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained. Pharmaceutically acceptable carriers or excipients have preferably met the required standards of toxicological and manufacturing testing and / or are included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.

[0374] The term “pharmaceutically acceptable salt” refers to a salt of any of the compounds herein which are known to be non-toxic and are commonly used in the pharmaceutical literature. In some embodiments, the pharmaceutically acceptable salt of a compound retains the biological effectiveness of the compounds described herein and are not biologically or otherwise undesirable. Examples of pharmaceutically acceptable salts can be found in Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1),1-19. Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, lactic acid, oxalic acid, malic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxy ethylsulfonic acid, p- toluenesulfonic acid, stearic acid and salicylic acid. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, and aluminum. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines; substituted amines including naturally occurring substituted amines; cyclic amines; and basic ion exchange resins. Examples of organic bases include isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is selected from ammonium, potassium, sodium, calcium, and magnesium salts.

[0375] If the compound described herein is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the compound is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds (see, e.g., Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January 1977, 66(1), 1-19). Those skilled in the art will recognize various synthetic methodologies that may be used to prepare pharmaceutically acceptable addition salts.

[0376] As used herein, “therapeutically effective amount” indicates an amount that results in a desired pharmacological and / or physiological effect for the condition. The effect may be prophylactic in terms of completely or partially preventing a condition or symptom thereof and / or may be therapeutic in terms of a partial or complete cure for the condition and / or adverse effect attributable to the condition.

[0377] The terms “treat,” “treating,” and “treatment” refer to an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired results include,but are not limited to, one or more of the following: decreasing one or more symptoms resulting from the disease or disorder, diminishing the extent of the disease or disorder, stabilizing the disease or disorder (e.g, preventing or delaying the worsening of the disease or disorder), delaying the occurrence or recurrence of the disease or disorder, delaying or slowing the progression of the disease or disorder, ameliorating the disease or disorder state, providing a remission (whether partial or total) of the disease or disorder, decreasing the dose of one or more other medications required to treat the disease or disorder, enhancing the effect of another medication used to treat the disease or disorder, delaying the progression of the disease or disorder, increasing the quality of life, and / or prolonging survival of a patient. Also encompassed by “treatment” is a reduction of pathological consequence of the disease or disorder. The methods of this disclosure contemplate any one or more of these aspects of treatment.

[0378] The term “subject” refers to an animal, including, but not limited to, a primate (e.g, human), monkey, cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse. The terms “subject” and “patient” are used interchangeably herein in reference, for example, to a mammalian subject, such as a human.V. EXEMPLARY EMBODIMENTS

[0379] Among the provided embodiments are:1. A method of treatment, the method comprising:(a) selecting a subject that has previously received a first calcineurin inhibitor (CNI) for immunosuppression for at least 30 days, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof; and(b) administering voclosporin to the selected subject.2. A method of treatment, the method comprising administering voclosporin to a subject that has previously received a first calcineurin inhibitor (CNI) for immunosuppression for at least 30 days, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.3. A method for selecting a subject for treatment with voclosporin, the method comprising selecting a subject that has previously received a first calcineurin inhibitor (CNI) for immunosuppression for at least 30 days, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.4. The method of any of embodiments 1-3, wherein the method further comprisesIllperforming one or more renal biopsies on the subject.5. The method of embodiment 4, wherein the one or more indicators of drug-induced nephrotoxicity is assessed based on the one or more renal biopsies.6. A method of reducing drug-induced nephrotoxicity, the method comprising:(a) selecting a subject that exhibits one or more indicators of drug-induced nephrotoxicity after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof; and(b) administering voclosporin to the selected subject.7. A method of reducing drug-induced nephrotoxicity, the method comprising administering voclosporin to a subject that exhibits one or more indicators of drug-induced nephrotoxicity after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.8. A method for selecting a subject for treatment with voclosporin, the method comprising selecting a subject that exhibits one or more indicators of drug-induced nephrotoxicity after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.9. The method of any of embodiments 6-8, wherein the one or more indicators of drug-induced nephrotoxicity is assessed based on one or more renal biopsies.10. A method of reducing drug-induced tubular dysfunction, the method comprising:(a) selecting a subject that exhibits one or more indicators of drug-induced tubular dysfunction after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof; and(b) administering voclosporin to the selected subject.11. A method of reducing drug-induced tubular dysfunction, the method comprising administering voclosporin to a subject that exhibits one or more indicators of drug-induced tubular dysfunction after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.12. A method for selecting a subject for treatment with voclosporin, the methodcomprising selecting a subject that exhibits one or more indicators of drug-induced tubular dysfunction after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.13. The method of any of embodiments 10-12, wherein the drug-induced tubular dysfunction comprises drug-induced hypercalcemia.14. A method of reducing drug-induced hypercalcemia, the method comprising:(a) selecting a subject that exhibits one or more indicators of drug-induced hypercalcemia after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof; and(b) administering voclosporin to the selected subject.15. A method of reducing drug-induced hypercalcemia, the method comprising administering voclosporin to a subject that exhibits one or more indicators of drug-induced hypercalcemia after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.16. A method for selecting a subject for treatment with voclosporin, the method comprising selecting a subject that exhibits one or more indicators of drug-induced hypercalcemia after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.17. The method of any of embodiments 1-16, wherein the subject is selected for administration of voclosporin if the subject exhibits a 10% or greater increase in fractional calcium excretion as assessed after receiving the first CNI, compared to a baseline fractional calcium excretion as assessed prior to receiving the first CNI.18. The method of any of embodiments 1-17, wherein the subject is selected for administration of voclosporin if the subject exhibits a 1.2-fold or greater increase in fractional magnesium excretion as assessed after receiving the first CNI, compared to a baseline fractional magnesium excretion as assessed pr...

Claims

Claims1. A method of treatment, the method comprising:(a) selecting a subject that has previously received a first calcineurin inhibitor (CNI) for immunosuppression for at least 30 days, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof; and(b) administering voclosporin to the selected subject.

2. A method of treatment, the method comprising administering voclosporin to a subject that has previously received a first calcineurin inhibitor (CNI) for immunosuppression for at least 30 days, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

3. A method for selecting a subject for treatment with voclosporin, the method comprising selecting a subject that has previously received a first calcineurin inhibitor (CNI) for immunosuppression for at least 30 days, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

4. The method of any of claims 1-3, wherein the method further comprises performing one or more renal biopsies on the subject.

5. The method of claim 4, wherein the one or more indicators of drug-induced nephrotoxicity is assessed based on the one or more renal biopsies.

6. A method of reducing drug-induced nephrotoxicity, the method comprising:(a) selecting a subject that exhibits one or more indicators of drug-induced nephrotoxicity after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof; and(b) administering voclosporin to the selected subject.

7. A method of reducing drug-induced nephrotoxicity, the method comprising administering voclosporin to a subject that exhibits one or more indicators of drug-induced nephrotoxicity after previously receiving a first calcineurin inhibitor (CNI) forimmunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

8. A method for selecting a subject for treatment with voclosporin, the method comprising selecting a subject that exhibits one or more indicators of drug-induced nephrotoxicity after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

9. The method of any of claims 6-8, wherein the one or more indicators of drug- induced nephrotoxicity is assessed based on one or more renal biopsies.

10. A method of reducing drug-induced tubular dysfunction, the method comprising:(a) selecting a subject that exhibits one or more indicators of drug-induced tubular dysfunction after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof; and(b) administering voclosporin to the selected subject.

11. A method of reducing drug-induced tubular dysfunction, the method comprising administering voclosporin to a subject that exhibits one or more indicators of drug-induced tubular dysfunction after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

12. A method for selecting a subject for treatment with voclosporin, the method comprising selecting a subject that exhibits one or more indicators of drug-induced tubular dysfunction after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

13. The method of any of claims 10-12, wherein the drug-induced tubular dysfunction comprises drug-induced hypercalcemia.

14. A method of reducing drug-induced hypercalcemia, the method comprising:(a) selecting a subject that exhibits one or more indicators of drug-induced hypercalcemia after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof; and(b) administering voclosporin to the selected subject.

15. A method of reducing drug-induced hypercalcemia, the method comprising administering voclosporin to a subject that exhibits one or more indicators of drug-induced hypercalcemia after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

16. A method for selecting a subject for treatment with voclosporin, the method comprising selecting a subject that exhibits one or more indicators of drug-induced hypercalcemia after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

17. The method of any of claims 1-16, wherein the subject is selected for administration of voclosporin if the subject exhibits a 10% or greater increase in fractional calcium excretion as assessed after receiving the first CNI, compared to a baseline fractional calcium excretion as assessed prior to receiving the first CNI.

18. The method of any of claims 1-17, wherein the subject is selected for administration of voclosporin if the subject exhibits a 1.2-fold or greater increase in fractional magnesium excretion as assessed after receiving the first CNI, compared to a baseline fractional magnesium excretion as assessed prior to receiving the first CNI.

19. The method of any of claims 1-18, wherein the subject is selected for administration of voclosporin if the subject exhibits a 33% or greater decrease in urine epidermal growth factor normalized to creatinine (uEGF / Cr) as assessed after receiving the first CNI, compared to a baseline uEGF / Cr as assessed prior to receiving the first CNI.

20. The method of any of claims 1-19, wherein the subject is selected for administration of voclosporin if the subject exhibits a 2-fold or greater decrease in the level of calbindin-D28K as assessed after receiving the first CNI, compared to a baseline level of calbindin-D28K as assessed prior to receiving the first CNI.

21. The method of any of claims 1-18, wherein the subject is selected for administration of voclosporin if the subject exhibits a 1.5-fold or greater decrease in the level of sodium-chloride cotransporter (NCC) as assessed after receiving the first CNI, compared to a baseline level of NCC as assessed prior to receiving the first CNI.

22. The method of any of claims 1-21, wherein the subject is selected for administration of voclosporin if the subject exhibits a 30% or greater decrease in the expression level of one or more genes selected from the group consisting of Slcl2a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8al, and Calbl, as assessed after receiving the first CNI, compared to a respective baseline expression level of the one or more genes as assessed prior to receiving the first CNI.

23. The method of any of claims 1-22, wherein the subject is selected for administration of voclosporin if the subject exhibits hypercal ciuria.

24. The method of any of claims 10-12, wherein the drug-induced tubular dysfunction comprises hyperkalemia.

25. The method of claim 24, wherein the hyperkalemia is identified by a serum potassium level of > 5 mmol / L.

26. The method of any of claims 10-12, wherein the drug-induced tubular dysfunction comprises hypomagnesemia.

27. The method of claim 26, wherein the hypomagnesemia is identified by a serum magnesium level less than 1.4 mg / dL.

28. The method of any of claims 10-12, wherein the drug-induced tubular dysfunction comprises hypophosphatemia.

29. A method of treatment, the method comprising:(a) selecting a subject that exhibits a 10% or greater increase in fractional calcium excretion as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline fractional calcium excretion as assessed prior to receiving the first CNI; and(b) administering voclosporin to the selected subject.

30. A method for selecting a subject for treatment with voclosporin, the method comprising selecting a subject that exhibits a 10% or greater increase in fractional calcium excretion as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline fractional calcium excretion as assessed prior to receiving the first CNI.

31. The method of any of claims 17-30, wherein the subject is selected for treatment if the subject exhibits a 20% or greater increase in fractional calcium excretion after receiving the first CNI.

32. The method of any of claims 17-31, wherein the subject is selected for treatment if the subject exhibits a 2-fold or greater increase in fractional calcium excretion after receiving the first CNI.

33. The method of any of claims 17-32, wherein the subject is selected for treatment if the subject exhibits a 3-fold or greater increase in fractional calcium excretion after receiving the first CNI.

34. A method of treatment, the method comprising:(a) selecting a subject that exhibits a 1.2-fold or greater increase in fractional magnesium excretion as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline fractional magnesium excretion as assessed prior to receiving the first CNI; and(b) administering voclosporin to the selected subject.

35. A method for selecting a subject for treatment with voclosporin, the method comprising selecting a subject that exhibits a 1.2-fold or greater increase in fractional magnesium excretion as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline fractional magnesium excretion as assessed prior to receiving the first CNI.

36. The method of any of claims 18-35, wherein the subject is selected for treatment if the subject exhibits a 1.5-fold or greater increase in fractional magnesium excretion after receiving the first CNI.

37. A method of treatment, the method comprising:(a) selecting a subject that exhibits a 33% or greater decrease in urine epidermal growth factor normalized to creatinine (uEGF / Cr) as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline uEGF / Cr as assessed prior to receiving the first CNI; and(b) administering voclosporin to the selected subject.

38. A method for selecting a subject for treatment with voclosporin, the method comprising selecting a subject that exhibits a 33% or greater decrease in urine epidermal growth factor normalized to creatinine (uEGF / Cr) as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprisescyclosporin, tacrolimus, or a derivative thereof, compared to a baseline uEGF / Cr as assessed prior to receiving the first CNI.

39. The method of any of claims 19-38, wherein the subject is selected for treatment if the subject exhibits a 40% or greater decrease in uEGF / Cr after receiving the first CNI.

40. A method of treatment, the method comprising:(a) selecting a subject that exhibits a 2-fold or greater decrease in the level of calbindin-D28K as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline level of calbindin-D28K as assessed prior to receiving the first CNI; and(b) administering voclosporin to the selected subject.

41. A method for selecting a subject for treatment with voclosporin, the method comprising selecting a subject that exhibits a 2-fold or greater decrease in the level of calbindin-D28K as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline level of calbindin-D28K as assessed prior to receiving the first CNI.

42. The method of any of claims 20-41, wherein the subject is selected for treatment if the subject exhibits a 3-fold or greater increase in the level of calbindin-D28K after receiving the first CNI.

43. A method of treatment, the method comprising:(a) selecting a subject that exhibits a 1.5-fold or greater decrease in the level of sodium-chloride cotransporter (NCC) as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline level of NCC as assessed prior to receiving the first CNI; and(b) administering voclosporin to the selected subject.

44. A method for selecting a subject for treatment with voclosporin, the method comprising selecting a subject that exhibits a 1.5-fold or greater decrease in the level of sodium-chloride cotransporter (NCC) as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline level of NCC as assessed prior to receiving the first CNI.

45. The method of any of claims 21-44, wherein the subject is selected for treatment if the subject exhibits a 2-fold or greater increase in the level of NCC after receiving the first CNI.

46. A method of treatment, the method comprising:(a) selecting a subject that exhibits a 30% or greater decrease in the expression level of one or more genes selected from the group consisting of Slcl2a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8al, and Calbl as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline expression level of the one or more genes as assessed prior to receiving the first CNI; and(b) administering voclosporin to the selected subject.

47. A method for selecting a subject for treatment with voclosporin, the method comprising selecting a subject that exhibits a 30% or greater decrease in the expression level of one or more genes selected from the group consisting of Slcl2a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8al, and Calbl as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof, compared to a baseline expression level of the one or more genes as assessed prior to receiving the first CNI.

48. The method of any of claims 22-47, wherein the subject is selected for treatment if the subject exhibits a 50% or greater decrease in the expression level of the one or more genes after receiving the first CNI.

49. A method of reducing drug-induced dyslipidemia, the method comprising:(a) selecting a subject that exhibits one or more indicators of drug-induced dyslipidemia after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof; and(b) administering voclosporin to the selected subject.

50. A method of reducing drug-induced dyslipidemia, the method comprising administering voclosporin to a subject that exhibits one or more indicators of drug-induced dyslipidemia after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

51. A method for selecting a subj ect for treatment with voclosporin, the method comprising selecting a subject that exhibits one or more indicators of drug-induced dyslipidemia after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

52. The method of any of claims 1-51, wherein the subject is selected for administration of voclosporin if the subject exhibits hypertriglyceridemia as assessed after receiving the first CNI.

53. The method of any of claims 1-52, wherein the subject is selected for administration of voclosporin if the subject exhibits a 30% or greater increase in the level of triacylglycerol (TAG), as assessed after receiving the first CNI, compared to a baseline level of TAG as assessed prior to receiving the first CNI.

54. The method of any of claims 1-53, wherein the subject is selected for administration of voclosporin if the subject exhibits a 30% or greater increase in the level of ceramides (CER), as assessed after receiving the first CNI, compared to a baseline level of CER as assessed prior to receiving the first CNI.

55. The method of any of claims 1-54, wherein the subject is selected for administration of voclosporin if the subject exhibits hypercholesterolemia as assessed after receiving the first CNI.

56. The method of any of claims 1-55, wherein the subject is selected for administration of voclosporin if the subject exhibits a 30% or greater increase in the level of low density lipoprotein (LDL) cholesterol, as assessed after receiving the first CNI, compared to a baseline level of LDL as assessed prior to receiving the first CNI.

57. A method of treatment, the method comprising:(a) selecting a subject that exhibits a reduction of blood levels of mycophenolic acid (MPA) after previously receiving a first calcineurin inhibitor (CNI) in combination with my cophenolate mofetil (MMF) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof; and(b) administering voclosporin to the selected subject.

58. A method of treatment, the method comprising administering voclosporin to a subject that exhibits a reduction of blood levels of mycophenolic acid (MPA) after previously receiving a first calcineurin inhibitor (CNI) in combination with my cophenolate mofetil (MMF) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

59. A method for selecting a subject for treatment with voclosporin, the method comprising selecting a subject that exhibits a reduction of blood levels of mycophenolic acid (MPA) after previously receiving a first calcineurin inhibitor (CNI) in combination with my cophenolate mofetil (MMF) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

60. The method of any of claims 1-58, wherein the subject is selected for administration of voclosporin if the subject exhibits a 1.5-fold or greater reduction in the blood levels of MPA, as assessed after receiving the first CNI, compared to a baseline blood level of MPA as assessed prior to receiving the first CNI.

61. The method of any of claims 57-60, wherein the blood levels of MPA are determined as the maximum serum concentration (Cmax) or area under the concentration curve from time 0 to 12 h (AUC0-12).

62. A method of reducing new-onset diabetes, the method comprising:(a) selecting a subject that exhibits one or more indicators of new-onset diabetes after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof; and(b) administering voclosporin to the selected subject.

63. A method of reducing new-onset diabetes, the method comprising administering voclosporin to a subject that exhibits one or more indicators of new-onset diabetes after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

64. A method for selecting a subject for treatment with voclosporin, the method comprising selecting a subject that exhibits one or more indicators of new-onset diabetes after previously receiving a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporin, tacrolimus, or a derivative thereof.

65. The method of any of claims 62-64, wherein the new-onset diabetes comprises new-onset diabetes after transplant (NODAT).

66. The method of any of claims 1-65, wherein the subject is selected for administration of voclosporin if the subject exhibits hyperglycemia.

67. The method of any of claims 1-66, wherein the subject is selected for administration of voclosporin if the subject exhibits islet cell death.

68. The method of any of claims 1-67, wherein the subject is selected for administration of voclosporin if the subject exhibits interstitial fibrosis and tubular atrophy in observed in > 5% in cortical area after receiving the first CNI, based on the renal biopsies.

69. The method of any of claims 1-68, wherein the subject is selected for administration of voclosporin if the subject exhibits medial arteriolar hyalinosis after receiving the first CNI, based on the renal biopsies.

70. The method of claim 69, wherein medial arteriolar hyalinosis is identified by the replacement of necrotic smooth muscle cells with focal, circular lumpy protein (hyaline) deposits at the periphery of the wall of afferent arterioles, and / or the narrowing of the vascular lumen.

71. The method of any of claims 1-70, wherein the subject is selected for administration of voclosporin if the subject exhibits glomerular injury medial arteriolar hyalinosis after receiving the first CNI, based on the renal biopsies.

72. The method of claim 71, wherein glomerular injury is identified by global and segmental glomerulosclerosis, tubular atrophy, interstitial fibrosis, and / or arteriosclerosis are observed; and / or the total renal chronicity score of > 1.

73. The method of any of claims 1-72, wherein the subject is selected for administration of voclosporin if the subject exhibits juxtaglomerular apparatus (JGA) after receiving the first CNI, based on the renal biopsies.

74. The method of claim 73, wherein JGA hyperplasia is identified by enlargements of juxtaglomerular apparatus components comprising one or more of: the vascular components, the mesangial cell components, the tubular components (the macula densa); and / or the presence of intracellular renin granules.

75. The method of any of claims 1-74, wherein the subject is selected for administration of voclosporin if the subject exhibits tubular microcalcifications after receiving the first CNI, based on the renal biopsies.

76. The method of any of claims 1-75, wherein the subject is selected for administration of voclosporin if the subject exhibits a 10% or greater loss of P-gly coprotein(P-gp) expression as assessed after receiving the first CNI, compared to a baseline P-gp expression as assessed prior to receiving the first CNI, based on the renal biopsies.

77. The method of any of claims 1-76, wherein the subject is selected for administration of voclosporin if the subject exhibits a Drug-induced nephrotoxicity score of Nephrotoxicity Score of 0-3 after receiving the first CNI, based on the renal biopsies.

78. The method of any of claims 1-77, wherein the subject is selected for administration of voclosporin if the subject exhibits a Banff score of 0-3 after receiving the first CNI, based on the renal biopsies.

79. The method of any of claims 1-78, wherein the subject is selected for administration of voclosporin if the subject exhibits an increase in the National Institutes of Health Activity Index (NIH-AI) from a renal biopsy as assessed after receiving the first CNI, compared to a baseline NIH-AI as assessed prior to receiving the first CNI, based on the renal biopsies.

80. The method of any of claims 1-79, wherein the subject is selected for administration of voclosporin if the subject exhibits a NIH-AI of 3 or higher after receiving the first CNI, based on the renal biopsies.

81. The method of any of claims 1-80, wherein the subject is selected for administration of voclosporin if the subject exhibits a 30% or greater increase in the National Institutes of Health Chronicity Index (NIH-CI) as assessed after receiving the first CNI, compared to a baseline NIH-CI as assessed prior to receiving the first CNI, based on the renal biopsies.

82. The method of any of claims 1-81, wherein the subject is selected for administration of voclosporin if the subject exhibits a 40% or greater increase in the NIH-CI, compared to the baseline NIH-CI, based on the renal biopsies.

83. The method of any of claims 1-82, wherein the subject is selected for administration of voclosporin if the subject exhibits a NIH-CI of 3 or higher after receiving the first CNI, based on the renal biopsies.

84. The method of any of claims 1-83, wherein the subject is selected for administration of voclosporin if the subject exhibits a 10% or greater increase in a Tubulointerstitial Activity Index (TIAI) as assessed after receiving the first CNI, compared to a baseline TIAI, based on the renal biopsies.

85. The method of any of claims 1-84, wherein the subject has previously received cyclosporin, tacrolimus, or derivative thereof for at least 30 days.

86. The method of any of claims 1-85, wherein the subject has previously received cyclosporin, tacrolimus, or derivative thereof for at least 30 days, at least 60 days, at least 90 days, at least 120 days, at least 150 days, at least 180 days, at least 1 year, at least 1.5 years, at least 2 years, at least 2.5 years, at least 3 years, or longer.

87. The method of any of claims 1-86, wherein the first CNI comprises cyclosporin.

88. The method of any of claims 1-87, wherein the first CNI comprises cyclosporine A.

89. The method of any of claims 1-86, wherein the first CNI comprises tacrolimus.

90. The method of any of claims 1-89, wherein the subject has previously received an organ transplant or is a candidate for an organ transplant.

91. The method of any of claims 1-90, wherein the subject has or has been diagnosed with a proteinuric kidney disease.

92. The method of any of claims 1-91, wherein the subject has or has been diagnosed with lupus nephritis (LN).

93. The method of any of claims 1-92, wherein the method further comprises discontinuing the administration of the first CNI, before beginning the administration of the voclosporin.

94. The method of any of claims 1-93, wherein the method further comprises administering voclosporin to the selected subject.

95. The method of any of claims 1-94, wherein the voclosporin is administered at a daily dose of between about 5 mg BID to about 50 mg BID.

96. The method of any of claims 1-95, wherein the voclosporin is administered at an initial daily dose of about 39.5 mg, about 31.6 mg, about 23.7 mg, about 15.8 mg, or about 7.9 mg BID.

97. The method of any of claims 1-96, wherein the voclosporin is administered at an initial daily dose of about 39.5 mg.

98. The method of any of claims 1-96, wherein the voclosporin is administered at an initial daily dose of about 23.7 mg.

99. The method of any of claims 1-96, wherein the voclosporin is administered at an initial daily dose of about 15.8 mg.

100. The method of any of claims 1-99, wherein the voclosporin is administered over a projected voclosporin treatment period of at least 3 months, at least 6 months, at least 9 months, at least 12 months, at least 18 months, at least 24 months, at least 36 months, or at least 48 months or longer.

101. The method of any of claims 1-100, wherein the method further comprises:(a) assessing the estimated Glomerular Filtration Rate (eGFR) of the subject at at least a first time point and a second time point on different days of the projected treatment period; and(b) (i) if the eGFR of the subject decreases by more than a target % to below a predetermined value, between the first and second time points, reducing the daily dose by increment(s) of 7.9 mg BID or stopping the administering of voclosporin;(ii) if the eGFR of the subject decreases by less than the target %, between the first and second time points, continuing administering the same predetermined daily dosage of voclosporin to the subject.

102. The method of claim 101, wherein the predetermined value is in the range of 50-90 ml / min / 1.73m2.

103. The method of claim 101 or 102, wherein the predetermined value is approximately 60 ml / min / 1.73m2.

104. The method of any of claims 101-103, wherein the target % is in the range of 20%-45%.

105. The method of any of claims 101-104, wherein the target % is approximately 30%.

106. The method of any of claims 101-105, wherein:(i) if the eGFR of the subject decreases by >30% to a value of below 60 mL / min / 1.73m2between the first and second time points, stopping the administering of voclosporin to the subject;(ii) if the eGFR of the subject decreases by between 20% to 30% to a value of below 60 ml / min / 1 ,73m2between the first and second time points, administering a reduced dosage of voclosporin to the subject; and(iii) if the eGFR of the subject decreases by <20% between the first and second time points, continuing administering the same predetermined daily dosage of voclosporin to the subject.

107. The method of any of claims 101-106, wherein the first time point is immediately preceding initiating the administration of voclosporin.

108. The method of any of claims 101-107, wherein the second time point is after the first time point and initiating the administration of voclosporin.

109. The method of any of claims 101-108, wherein the second time point is 8 weeks after initiating the administration of voclosporin.

110. The method of any of claims 101-109, wherein the method further comprises determining the eGFR of the subject at a third time point and if the eGFR is determined at the third time point to differ from the eGFR determined at the first time point by less than the target %, resuming administering the predetermined daily dosage of voclosporin.

111. The method of any of claims 101-110, wherein the method further comprises:(a) measuring urinary protein creatinine ratio (UPCR) of the subject at the first time point and the second time point and determining any reduction of the UPCR between the first and second time points, and(b) if the UPCR of the subject fails to show a reduction of at least 25% at the second time point, discontinuing administering voclosporin to the subject.

112. The method of any of claims 101-111, wherein the method further comprises measuring the concentration of C3 or C4 in the blood of the subject at the first time point and the second time point, and determining whether the concentration of C3 or C4 is normalized at the second time point, and if normalization of C3 or C4 is found, reinstating the administering voclosporin to the subject.

113. The method of any of claims 1-112, wherein the method further comprises administering to the subject an effective amount of my cophenolate mofetil (MMF).

114. The method of any of claims 1-113, wherein the method further comprises administering to the subject an effective amount of a corticosteroid.

115. The method of any of claims 1-114, wherein the voclosporin is a mixture of at least 90% E isomer and not more than 10% Z isomer.

116. Voclosporin for use in the method of any of claims 1-115.

117. Use of voclosporin in the manufacture of a medicament according to the method of any of claims 1-115.

118. Use of voclosporin in the method of any of claims 1-115.

Images