Methods and uses related to the administration of voclosporine

Abstract

This specification provides methods and uses of treatment involving the administration of voclosporine to subjects who have previously received a calcineurin inhibitor (CNI), such as cyclosporine, tacrolimus, or derivatives thereof, for immunosuppression. In some embodiments, the methods and uses relate to selecting subjects who have previously received a CNI, such as cyclosporine, tacrolimus, or derivatives thereof, for immunosuppression, for the administration of voclosporine. In some embodiments, the methods and uses relate to treating or mitigating adverse effects that may be associated with immunosuppression using a CNI, such as cyclosporine, tacrolimus, or derivatives thereof. In some embodiments, the methods and uses include administering a therapeutically effective dose of voclosporine to the selected subjects.

Description

Technical Field

[0001] Cross - reference to Related Applications This application claims priority based on U.S. Provisional Application Nos. 63 / 457,084 filed on April 4, 2023, 63 / 500,236 filed on May 4, 2023, 63 / 501,361 filed on May 10, 2023, and 63 / 513,708 filed on July 14, 2023 (all entitled "METHODS AND USES RELATED TO ADMINISTRATION OF VOCLOSPORIN"), the contents of which are hereby incorporated by reference in their entirety.

[0002] The present disclosure relates to methods of treatment and uses including the administration of voclosporin to subjects who have previously received a calcineurin inhibitor (CNI) such as cyclosporine, tacrolimus, or derivatives thereof for immunosuppression. In some aspects, the methods and uses herein relate to selecting subjects who have previously received a CNI such as cyclosporine, tacrolimus, or derivatives thereof for immunosuppression for administration of voclosporin. In some aspects, the methods herein relate to treating or reducing adverse effects that may be associated with immunosuppression using a CNI such as cyclosporine, tacrolimus, or derivatives thereof. In some aspects, the methods and uses herein include administering a therapeutically safe and effective amount of voclosporin to a selected subject.

Background Art

[0003] Both cyclosporine and tacrolimus are potent immunosuppressive agents, and conventional CNIs such as these have been tested for use in the treatment of various conditions, including in combination with tissue transplantation. Both of these compounds exhibit long - term nephrotoxicity. There is a need for a CNI that is an effective immunosuppressive agent and can withstand long - term use. Methods and uses that satisfy such a need are provided herein.

Summary of the Invention

[0004] This specification provides methods and uses relating to therapies using voclosporine. In some embodiments, the methods and uses relate to administering voclosporine to subjects who have previously received different calcineurin inhibitors (CNIs), such as cyclosporine, tacrolimus, or derivatives thereof, which may be referred to as conventional CNIs. Methods and uses relating to the selection of subjects for treatment using voclosporine are also provided. In some embodiments, the methods and uses relate to selecting subjects who have previously received different CNIs, such as cyclosporine, tacrolimus, or derivatives thereof, which may be referred to as conventional CNIs. In some embodiments, voclosporine is administered to the selected subjects.

[0005] This specification provides a method of treatment comprising selecting a subject who has previously received a first CNI for immunosuppression for at least 30 days, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof, and administering voclosporine to the selected subject.

[0006] Also provided is a method of treatment comprising administering voclosporine to a subject who has previously received a first CNI for immunosuppression for at least 30 days, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0007] Also provided is a method for selecting subjects for treatment with voclosporine, comprising selecting subjects who have previously received a first CNI for immunosuppression for at least 30 days, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0008] In some embodiments, the method also includes performing one or more renal biopsies on a subject. In some embodiments, one or more indicators of drug-induced nephrotoxicity are evaluated based on the one or more renal biopsies.

[0009] Also provided is a method for mitigating drug-induced nephrotoxicity, comprising selecting a subject who exhibits one or more indicators of drug-induced nephrotoxicity after having previously received a first CNI for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof, and administering voclosporine to the selected subject.

[0010] Also provided is a method for mitigating drug-induced nephrotoxicity, comprising administering voclosporine to a subject exhibiting one or more indicators of drug-induced nephrotoxicity after having previously received a first CNI for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0011] Also provided is a method for selecting subjects for treatment with voclosporine, comprising selecting subjects who exhibit one or more indicators of drug-induced nephrotoxicity after having previously received a first CNI for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0012] In some embodiments, one or more indicators of drug-induced nephrotoxicity are assessed based on one or more renal biopsies.

[0013] Also provided is a method for mitigating drug-induced tubular dysfunction, comprising selecting a subject who exhibits one or more indicators of drug-induced tubular dysfunction after having previously received a first CNI for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof, and administering voclosporine to the selected subject.

[0014] Also provided is a method for alleviating drug-induced tubular dysfunction, comprising administering voclosporine to a subject exhibiting one or more indicators of drug-induced tubular dysfunction after prior treatment with a first CNI for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0015] Also provided is a method for selecting subjects for treatment with voclosporine, comprising selecting subjects who exhibit one or more indicators of drug-induced tubular dysfunction after having previously received a first CNI for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0016] In some embodiments, drug-induced tubular dysfunction includes drug-induced hypercalcemia.

[0017] Also provided is a method for mitigating drug-induced hypercalcemia, comprising selecting a subject who exhibits one or more indicators of drug-induced hypercalcemia after having previously received a first CNI for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof, and administering voclosporine to the selected subject.

[0018] Also provided is a method for mitigating drug-induced hypercalcemia, comprising administering voclosporine to a subject exhibiting one or more indicators of drug-induced hypercalcemia after prior receipt of a first CNI for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0019] Also provided is a method for selecting subjects for treatment with voclosporine, comprising selecting subjects who exhibit one or more indicators of drug-induced hypercalcemia after having previously received a first CNI for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0020] In some embodiments, a subject is selected for voclosporine administration if the subject shows a 10% or greater increase in the fractional calcium excretion rate assessed after receiving the first CNI compared to the baseline fractional calcium excretion rate assessed before receiving the first CNI. In some embodiments, a subject is selected for voclosporine administration if the subject shows a 2-fold or greater increase in the fractional calcium excretion rate assessed after receiving the first CNI compared to the baseline fractional calcium excretion rate assessed before receiving the first CNI.

[0021] In some embodiments, a subject is selected for voclosporine administration if their magnesium fractional excretion rate, as assessed after receiving the first CNI, shows an increase of 1.2 times or more compared to their baseline magnesium fractional excretion rate assessed before receiving the first CNI.

[0022] In some embodiments, a subject is selected for voclosporine administration if their creatinine-normalized urinary epidermal growth factor (uEGF / Cr), assessed after receiving the first CNI, shows a decrease of 33% or more compared to their baseline uEGF / Cr assessed before receiving the first CNI.

[0023] In some embodiments, a subject is selected for voclosporine administration if their calbindin-D28K level, assessed after receiving the first CNI, shows a decrease of more than twofold compared to their baseline calbindin-D28K level assessed before receiving the first CNI.

[0024] In some embodiments, a subject is selected for voclosporine administration if their sodium chloride cotransporter (NCC) level, as assessed after receiving the first CNI, shows a decrease of 1.5 times or more compared to the baseline NCC level assessed before receiving the first CNI.

[0025] In some embodiments, a subject is selected for voclosporine administration if, after receiving a first CNI, the expression level of one or more genes selected from the group consisting of Slc12a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8a1, and Calb1 is reduced by 30% or more compared to the baseline expression level of each of those genes as assessed before receiving the first CNI.

[0026] In some embodiments, if a subject exhibits hypercalciuria, the subject is selected for administration of voclosporine.

[0027] In some embodiments, drug-induced tubular dysfunction includes hyperkalemia. In some embodiments, hyperkalemia is identified by a serum potassium level greater than 5 mmol / L.

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

[0029] In some embodiments, drug-induced tubular dysfunction includes hypophosphatemia.

[0030] Also provided is a treatment method comprising selecting subjects who show an increase of 10% or more in the fractional calcium excretion rate evaluated after receiving a first CNI for immunosuppression compared to the baseline fractional calcium excretion rate evaluated before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof, and administering voclosporine to the selected subjects.

[0031] Also provided is a method for selecting subjects for treatment with voclosporine, comprising selecting subjects who show an increase of 10% or more in the calcium fraction excretion rate evaluated after receiving a first CNI for immunosuppression compared to the baseline calcium fraction excretion rate evaluated before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0032] In some embodiments, a subject is selected for treatment if, after receiving the first CNI, the subject shows an increase of 20% or more in the calcium fraction excretion rate.

[0033] Also provided is a method of treatment comprising selecting subjects whose calcium fractional excretion rate, as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, shows a twofold or greater increase compared to a baseline calcium fractional excretion rate assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof, and administering voclosporine to the selected subjects.

[0034] Also provided is a method for selecting subjects for treatment with voclosporine, comprising selecting subjects who show a twofold or greater increase in calcium fractional excretion rate, as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, compared to a baseline calcium fractional excretion rate assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0035] In some embodiments, a subject is selected for treatment if, after receiving a first CNI, the subject shows a threefold or greater increase in calcium fraction excretion rate.

[0036] Also provided is a treatment method comprising selecting subjects whose magnesium fractional excretion rate, as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, shows an increase of 1.2 times or more compared to the baseline magnesium fractional excretion rate assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof, and administering voclosporine to the selected subjects.

[0037] Also provided is a method for selecting subjects for treatment with voclosporine, comprising selecting subjects who show a 1.2-fold or greater increase in magnesium fractional excretion rate, as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, compared to a baseline magnesium fractional excretion rate assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0038] In some embodiments, a subject is selected for treatment if, after receiving the first CNI, the subject shows an increase of 1.5 times or more in the magnesium fractional excretion rate.

[0039] Also provided is a treatment method comprising selecting subjects who show a decrease of 33% or more in creatinine-normalized urinary epidermal growth factor (uEGF / Cr) assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, compared to baseline uEGF / Cr assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof, and administering voclosporine to the selected subjects.

[0040] Also provided is a method for selecting subjects for treatment with voclosporine, comprising selecting subjects who show a decrease of 33% or more in creatinine-normalized urinary epidermal growth factor (uEGF / Cr) assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, compared to baseline uEGF / Cr assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0041] In some embodiments, a subject is selected for treatment if they show a decrease of 40% or more in uEGF / Cr after receiving a first CNI.

[0042] Also provided is a method of treatment comprising selecting subjects whose calbindin-D28K levels, as assessed after receiving a first CNI for immunosuppression, show a decrease of more than twofold compared to baseline levels of calbindin-D28K assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof, and administering voclosporine to the selected subjects.

[0043] Also provided is a method for selecting subjects for treatment with voclosporine, comprising selecting subjects who show a decrease of more than twofold in the level of calbindin-D28K assessed after receiving a first CNI for immunosuppression compared to the baseline level of calbindin-D28K assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0044] In some embodiment, a subject is selected for treatment if, after receiving a first CNI, the subject shows a threefold or greater increase in the level of calbindin-D28K.

[0045] Also provided is a treatment method comprising selecting subjects whose sodium chloride cotransporter (NCC) levels, as assessed after receiving a first CNI for immunosuppression, show a decrease of 1.5 times or more compared to baseline NCC levels assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof, and administering voclosporine to the selected subjects.

[0046] Also provided is a method for selecting subjects for treatment with voclosporine, comprising selecting subjects who show a decrease of 1.5 times or more in sodium chloride cotransporter (NCC) levels assessed after receiving a first CNI for immunosuppression compared to baseline NCC levels assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0047] In some embodiments, a subject is selected for treatment if, after receiving a first CNI, the subject shows a twofold or greater increase in NCC levels.

[0048] Also provided is a method of treatment comprising selecting subjects whose expression levels, as evaluated after receiving a first calcineurin inhibitor (CNI) for immunosuppression, are 30% or more lower than the baseline expression levels of one or more genes selected from the group consisting of Slc12a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8a1, and Calb1, compared to the baseline expression levels of said one or more genes evaluated before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof, and administering voclosporine to the selected subjects.

[0049] Also provided is a method for selecting subjects for voclosporine therapy, comprising selecting subjects whose expression levels, as evaluated after receiving a first calcineurin inhibitor (CNI) for immunosuppression, are 30% or more lower than the baseline expression levels of one or more genes selected from the group consisting of Slc12a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8a1, and Calb1, compared to the baseline expression levels of said one or more genes evaluated before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or derivatives thereof.

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

[0051] Also provided is a method for alleviating drug-induced dyslipidemia, comprising selecting a subject who exhibits one or more indicators of drug-induced dyslipidemia after having previously received a first CNI for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof, and administering voclosporine to the selected subject.

[0052] Also provided is a method for alleviating drug-induced dyslipidemia, comprising administering voclosporine to a subject exhibiting one or more indicators of drug-induced dyslipidemia after prior treatment with a first CNI for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0053] Also provided is a method for selecting subjects for treatment with voclosporine, comprising selecting subjects who exhibit one or more indicators of drug-induced dyslipidemia after having previously received a first CNI for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0054] In some embodiments, a subject is selected for voclosporine administration if they exhibit hypertriglyceridemia in an assessment after receiving a first CNI. In some embodiments, a subject is selected for voclosporine administration if their triacylglycerol (TAG) levels, assessed after receiving a first CNI, show an increase of 30% or more compared to their baseline TAG levels assessed before receiving a first CNI.

[0055] In some embodiments, a subject is selected for voclosporine administration if their ceramide (CER) level, as assessed after receiving the first CNI, shows an increase of 30% or more compared to their baseline CER level as assessed before receiving the first CNI.

[0056] In some embodiments, a subject is selected for voclosporine administration if they exhibit hypercholesterolemia in an assessment after receiving a first CNI. In some embodiments, a subject is selected for voclosporine administration if their low-density lipoprotein (LDL) cholesterol level, assessed after receiving a first CNI, shows an increase of 30% or more compared to their baseline LDL level assessed before receiving a first CNI.

[0057] Also provided is a method of treatment comprising selecting a subject who shows a decrease in blood levels of mycophenolate (MPA) after having previously received a first CNI in combination with mycophenolate mofetil (MMF) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof, and administering voclosporine to the selected subject.

[0058] Also provided is a method of treatment comprising administering voclosporine to a subject who shows a decrease in blood levels of mycophenolate (MPA) after having previously received a first CNI in combination with mycophenolate mofetil (MMF) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0059] Also provided is a method for selecting subjects for treatment with voclosporine, comprising selecting subjects who show a decrease in blood levels of mycophenolate (MPA) after prior treatment with a first CNI in combination with mycophenolate mofetil (MMF) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0060] In some embodiments, a subject is selected for voclosporine administration if their blood MPA level, assessed after receiving the first CNI, is 1.5 times or greater than their baseline blood MPA level assessed before receiving the first CNI. In some embodiments, the blood MPA level is the peak serum concentration (C max ) or area under the concentration curve (AUC) from 0 to 12 hours 0-12 It will be determined as follows.

[0061] Also provided is a method for mitigating new-onset diabetes, comprising selecting subjects who exhibit one or more indicators of new-onset diabetes after having previously received a first CNI for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof, and administering voclosporine to the selected subjects.

[0062] Also provided is a method for reducing new-onset diabetes, comprising administering voclosporine to a subject exhibiting one or more indicators of new-onset diabetes after prior treatment with a first CNI for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0063] Also provided is a method for selecting subjects for treatment with voclosporine, comprising selecting subjects who exhibit one or more indicators of new-onset diabetes after prior receipt of a first CNI for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0064] In some embodiments, newly diagnosed diabetes mellitus includes newly diagnosed diabetes mellitus post-transplant (NODAT). In some embodiments, subjects are selected for voclosporine administration if they exhibit hyperglycemia. In some embodiments, subjects are selected for voclosporine administration if they exhibit islet cell death.

[0065] In some embodiments, a subject is selected for voclosporine administration if, based on renal biopsy, the subject exhibits interstitial fibrosis and tubular atrophy observed in more than 5% of the cortical region after undergoing a first CNI. In some embodiments, a subject is selected for voclosporine administration if, based on renal biopsy, the subject exhibits arterioleomedia hyalinization after undergoing a first CNI. In some embodiments, arterioleomedia hyalinization is identified by the replacement of necrotic smooth muscle cells in the outer margin of the afferent arteriole wall with localized circular masses of protein (hyaluronic acid) deposits and / or narrowing of the vascular lumen. In some embodiments, a subject is selected for voclosporine administration if, based on renal biopsy, the subject exhibits glomerular injury arterioleomedia hyalinization after undergoing a first CNI. In some embodiments, glomerular injury is identified by the observation of whole-segmental and segmental glomerulosclerosis, tubular atrophy, interstitial fibrosis, and / or arteriosclerosis, and / or a total renal chronicity score > 1. In some embodiments, a subject is selected for voclosporine administration if, based on renal biopsy, the subject exhibits juxtaglomerular apparatus (JGA) after undergoing a first CNI. In some embodiments, JGA hyperplasia is identified by hypertrophy of components of the juxtaglomerular apparatus, including one or more of the vascular component, mesangial cellular component, and tubular component (macula densa), and / or the presence of intracellular renin granules. In some embodiments, a subject is selected for voclosporine administration if, based on renal biopsy, the subject exhibits tubular microcalcification after undergoing a first CNI. In some embodiments, a subject is selected for voclosporine administration if, based on renal biopsy, the subject shows a loss of 10% or more in P-glycoprotein (P-gp) expression assessed after receiving the first CNI compared to baseline P-gp expression assessed before receiving the first CNI. In some embodiments, a subject is selected for voclosporine administration if, based on renal biopsy, the subject shows a drug-induced nephrotoxicity score of 0 to 3 after receiving the first CNI.In some embodiments, a subject is selected for voclosporine administration if, based on a renal biopsy, the subject exhibits a Banff score of 0–3 after undergoing a first CNI.

[0066] In some embodiments, a subject is selected for voclosporine administration if, based on a renal biopsy, the subject shows an increase in the National Institutes of Health Activity Index (NIH-AI) at the renal biopsy assessed after the first CNI compared to the baseline NIH-AI assessed before the first CNI. In some embodiments, a subject is selected for voclosporine administration if, based on a renal biopsy, the subject shows an NIH-AI of 3 or higher after the first CNI.

[0067] In some embodiments, a subject is selected for voclosporine administration if, based on a renal biopsy, the subject shows a 30% or greater increase in the National Institutes of Health Chronicity Index (NIH-CI) assessed after receiving a first CNI compared to a baseline NIH-CI assessed before receiving the first CNI. In some embodiments, a subject is selected for voclosporine administration if, based on a renal biopsy, the subject shows a 40% or greater increase in NIH-CI compared to a baseline NIH-CI. In some embodiments, a subject is selected for voclosporine administration if, based on a renal biopsy, the subject shows an NIH-CI of 3 or greater after receiving a first CNI.

[0068] In some embodiments, a subject is selected for voclosporine administration if, based on a renal biopsy, the subject shows an increase of 10% or more in tubulointerstitial activity index (TIAI) assessed after receiving a first CNI compared to baseline TIAI.

[0069] In some embodiments, the subject has previously received cyclosporine, tacrolimus, or a derivative thereof for at least 30 days. In some embodiments, the subject has previously received cyclosporine, tacrolimus, or a 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 embodiments, the first CNI includes cyclosporine. In some embodiments, the first CNI includes cyclosporine A.

[0071] In some embodiment, the first CNI includes tacrolimus.

[0072] In some embodiments, the subjects are either previously recipients of organ transplants or candidates for organ transplants.

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

[0074] In some embodiment, the method also includes discontinuing the administration of the first CNI before initiating the administration of voclosporine.

[0075] In some embodiment, the method also includes administering voclosporine to a selected subject.

[0076] In some embodiments, voclosporine is administered in a daily dose of approximately 5 mg BID to approximately 50 mg BID. In some embodiments, voclosporine is administered in an initial daily dose of approximately 39.5 mg, approximately 31.6 mg, approximately 23.7 mg, approximately 15.8 mg, or approximately 7.9 mg BID. In some embodiments, voclosporine is administered in an initial daily dose of approximately 39.5 mg. In some embodiments, voclosporine is administered in an initial daily dose of approximately 23.7 mg. In some embodiments, voclosporine is administered in an initial daily dose of approximately 15.8 mg.

[0077] In some embodiments, voclosporine is administered over a planned voclosporine 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 part of any embodiment, the method also includes assessing the subject's estimated glomerular filtration rate (eGFR) at at least a first and second time point on separate days of a planned treatment period, and if the subject's eGFR falls significantly below a target percentage between the first and second time points to a predetermined value, reducing the daily dose in 7.9 mg BID increments or discontinuing voclosporine administration, and continuing administration of the same predetermined daily dose of voclosporine to the subject if the subject's eGFR falls less than a target percentage between the first and second time points.

[0079] In some embodiments, the predetermined values ​​are 50-90 ml / min / 1.73 m 2 It is within the range. In some embodiments, the given value is approximately 60 ml / min / 1.73 m 2 That is the case.

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

[0081] In some embodiments, the target eGFR decreases by more than 30% between the first and second time points to 60 mL / min / 1.73 m². 2 If the value falls below a certain level, administration of voclosporine to the subject should be stopped, and the subject's eGFR should decrease by 20% to 30% between the first and second time points to 60 ml / min / 1.73m². 2 If the value falls below a certain level, the reduced dose of voclosporine is administered to the subject. If the subject's eGFR decreases by less than 20% between the first and second time points, administration of the same prescribed daily dose of voclosporine is continued.

[0082] In some embodiments, the first time point is immediately before the start of voclosporine administration. In some embodiments, the second time point is after the first time point and after the start of voclosporine administration. In some embodiments, the second time point is 8 weeks after the start of voclosporine administration.

[0083] In part of any embodiment, the method also includes determining the target eGFR at a third time point, and if the eGFR at the third time point is determined to differ from the eGFR determined at the first time point by a smaller percentage than the target percentage, resuming administration of a predetermined daily dose of voclosporine.

[0084] In part of any embodiment, the method also includes measuring the urinary protein-creatinine ratio (UPCR) of the subject at a first time point and a second time point, determining whether there is a decrease in the UPCR between the first and second time points, and discontinuing the administration of voclosporine to the subject if the subject's UPCR does not show a decrease of at least 25% at the second time point.

[0085] In part of any embodiment, the method also includes measuring the concentration of C3 or C4 in the subject's blood at a first time point and a second time point, determining whether the concentration of C3 or C4 has normalized at the second time point, and, if normalization of C3 or C4 is found, resuming administration of voclosporine to the subject.

[0086] In some embodiment, the method also includes administering an effective amount of mycophenolate mofetil (MMF) to the subject.

[0087] In some embodiment, the method also includes administering an effective amount of corticosteroid to a target.

[0088] In some embodiments, the voclosporine is a mixture of at least 90% E isomer and 10% or less Z isomer.

[0089] Furthermore, this specification also provides boxrosporin for use in any of the methods provided.

[0090] This specification also provides the use of voclosporine in the manufacture of pharmaceuticals according to one of the methods provided.

[0091] Furthermore, this specification also provides the use of boxrosporin in any of the methods provided. [Brief explanation of the drawing]

[0092] [Figure 1] The diagram above shows a schematic of a clinical trial comparing the safety and efficacy of voclosporine at 24 and 48 weeks with placebo in subjects receiving mycophenolate mofetil (MMF) and oral corticosteroids in combination, and the tapering protocol used in the trial (bottom diagram). [Figure 2]A schematic diagram of the long-term safety and tolerability follow-up study is shown. As illustrated, 216 of the 357 subjects included in the one-year initial study advanced to the follow-up study. Baseline and repeat biopsy timings for the subject subgroups are also shown. [Figure 3] This shows the mean estimated glomerular filtration rate (eGFR) for 116 subjects in the voclosporine group and 100 subjects in the control group over a period of 36 months, including an additional 4-week follow-up period. The number of subjects in each study group at the same time point is also shown. [Figure 4] This report shows the mean adjusted estimated glomerular filtration rate (eGFR; 95% confidence interval) and the mean change in adjusted eGFR from pre-treatment baseline for 116 subjects in the voclosporine group and 100 subjects in the control group over a period including 36 months and an additional 4-week follow-up period. The number of subjects in each study group at the same time point is also shown. Pre-treatment baseline was defined as the last value before the subject received the first dose of the study drug on day 1 of the initial 12-month study (e.g., the beginning of the 36-month period). [Figure 5] This report shows the mean adjusted estimated glomerular filtration rate (eGFR) slope and the mean change in eGFR from month 12 (95% confidence interval) for 116 subjects in the voclosporine group and 100 subjects in the control group over a 24-month period (i.e., from month 12 to month 36). The mean adjusted eGFR slope and eGFR change were 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 group at the same point in time is also shown. [Figure 6] This shows the mean UPCR (mg / mg) for 116 subjects in the voclosporine group and 100 subjects in the control group over a period including 36 months and an additional 4-week follow-up (FUP). The number of subjects in each study group at the same time point is also shown. [Figure 7] The percentage of subjects with a 50% reduction in UPCR is shown every 6 months for 36 months, including an additional 4-week follow-up period. The number of subjects in each study group at the same time point is also shown. [Figure 8]The mean urinary protein-creatinine ratio (UPCR) is shown for a subgroup of 26 subjects (16 in the voclosporine group and 10 in the control group) evaluated by repeated renal biopsies during the 3-year trial, as well as for the total of 357 subjects investigated in this study. [Figure 9] The mean estimated glomerular filtration rate (eGFR) is shown for a subgroup of 26 subjects (16 in the voclosporine group and 10 in the control group) evaluated by repeated renal biopsies during the 3-year trial, as well as for the total of 357 subjects investigated in this study. [Figure 10] This report presents the least squares mean of adjusted estimated glomerular filtration rate (eGFR) for a subgroup of 26 subjects (16 in the voclosporine group and 10 in the control group) evaluated by repeated renal biopsies during the 3-year trial, and for the larger total trial group (n=216) for the 2-year extension trial. Renal function was assessed using the adjusted eGFR (formula for the Chronic Kidney Disease Epidemiological Collaborative Study) with a pre-specified upper limit of 90 mL / min / 1.73m2. [Figure 11] A and B are box plots showing disease activity (A; assessed based on renal biopsy evaluating the NIH-AI activity index by the National Institutes of Health; scale 0-24) and chronicity (B; assessed based on renal biopsy evaluating the NIH-CI chronicity index by the National Institutes of Health; scale 0-12) at baseline (BL) and follow-up (approximately 18 months after voclosporine treatment) for a subgroup of 26 subjects (16 in the voclosporine group and 10 in the control group) in a 3-year trial. The symbol "x" represents the mean, and the thick horizontal line represents the median. The upper and lower boxes represent the 75th and 25th percentiles, respectively. Outliers are represented by individual dots. [Figure 12-1]A shows the fractional calcium excretion rate in animals that received daily injections of either tacrolimus or voclosporine, compared to the media control, in terms of the magnification change. B shows the fractional magnesium excretion rate in animals that received daily injections of either tacrolimus or voclosporine, compared to the media control, in terms of the magnification change. C shows the serum magnesium level in nmol / L in animals that received injections of the media, tacrolimus, or voclosporine, and D shows the creatinine-normalized urinary epidermal growth factor (uEGF / Cr) in μg / mmol in the same animals. [Figure 12-2] E shows the sodium fractional excretion rate in animals receiving daily injections of either tacrolimus or voclosporine, in terms of the multiplier change compared to the media control. F shows the chloride fractional excretion rate in animals receiving daily injections of either tacrolimus or voclosporine, in terms of the multiplier change compared to the media control. Calculated values ​​are normalized to the mean of the media group, defined as 1.0. Shown are the data points and the mean ± SD (*P<0.05, **P<0.01, ***P<0.001, NS: not significant, one-way ANOVA and Dunnett's T3 post-hoc test). [Figure 12-3] G shows immunoblotting of whole-renal homogenates for sodium-chloride cotransporter (NCC)-combinant, calbindin-D28K, calcium channel TRPV5, calcium channel TRPM6, and GAPDH (control) in animals that received daily intraperitoneal injections of the medium, tacrolimus, or voclosporine. [Figure 12-4] H shows the densitometry analysis of the immunoblot. Relative protein abundance as band intensity (mean ± shown relative to the medium group (defined as 1.0)) is normalized to the mean intensity of the medium group. ** indicates P < 0.01 vs. medium, and *** indicates P < 0.001 vs. medium. [Figure 12-5]I shows immunoblotting of whole-renal homogenates for sodium-chloride cotransporter (NCC)-totally, pNCC-T53 (phosphorylated with threonine 53), carbindin-D28K, and sodium-calcium exchange transporter NCX1, as well as GAPDH (control), in animals that received daily intraperitoneal injections of the medium, tacrolimus, or voclosporine. [Figure 12-6] J shows the densitometry analysis of the immunoblots shown in Figure 12I and additional immunoblots not shown in Figure 12I. Band intensities are normalized to GAPDH and to the mean intensity of the media group defined as 1.0. The values ​​shown are mean ± SD (one-way ANOVA and Dunnett's T3 post-hoc test). [Figure 12-7] K represents the relative mRNA expression levels of the solute carrier family 12 member A3 (Slc12a3) gene, transient receptor potential cation channel subfamily M member 6 (Trpm6) gene, Cnnm2 (cyclin and CBS domain divalent metal cation transporter mediator 2) gene, epidermal growth factor (Egf) gene, calcium channel TRPV5 gene, solute carrier family 8 member A1 (Slc8A1) gene, and calbindin 1 (Calb1) gene in animals treated with either tacrolimus or voclosporine, compared to the expression levels shown in media control animals. Gene expression was normalized to Actb and to the mean value of the media group defined as 1.0. The data points and mean ± SD are shown (*P<0.05, **P<0.01, ***P<0.001, NS: not significant, one-way ANOVA and Dunnett's T3 post-hoc test, except Cnnm2 and Trpv5 which were performed using the Kruskal-Wallis test). [Figure 12-8]L shows the natriuretic response to hydrochlorothiazide on day 20. M shows the saline diuretic response to hydrochlorothiazide on day 20. The natriuretic and saline diuretic responses shown represent the 6-hour effect of a single dose of hydrochlorothiazide (25 mg / kg ip) on the change (Δ) in urinary Na+ and Cl- excretion, respectively. The values ​​shown are mean ± SD (one-way ANOVA and Dunnett's T3 post-hoc test, Δ: thiazide-medium. Data were acquired on day 19 for the medium and day 20 for thiazide). *P<0.05, **P<0.01, ***P<0.001, NS: not significant. [Figure 12-9] N and O indicate the effects of tacrolimus and voclosporine on endothelin-1 and cyclooxygenase-2 (COX-2) after 28 days of treatment. N represents plasma endothelin-1 (pg / ml). O represents relative COX-2 mRNA expression. Gene expression was normalized to Actb and the mean of the media group defined as 1.0. Data points and mean ± SD are shown (endothelin-1: one-way ANOVA and Dunnett's T3 post-hoc test; COX-2 mRNA: one-way ANOVA and Kruskal-Wallis test). *P<0.05, **P<0.01, ***P<0.001, NS: not significant. [Figure 13] Figures A-C show insulin secretion from human pancreatic islets treated with VCS and TAC at peak and trough concentrations. Figure A shows the averaged trace of dynamic insulin secretion measurements for 3 mM glucose, 15 mM glucose, or 30 mM KCl (as shown). Figure B shows the total area under the curve (AUC) for the response to 15 mM glucose. Figure C shows the total AUC for the response to KCl. [Figure 14] This shows the viability of human dispersed islet-derived pancreatic cells treated with VCS and TAC. The plots shown are normalized measures of maximum cell death for each TAC and VCS dose, normalized to a DMSO control culture. The results shown are quantified from five cultures for each drug condition in two separate experiments. [Figure 15]The results of RNA sequencing analysis of human pancreatic islets treated with peak doses of TAC and VCS are shown. Nominally differentially expressed mRNA (adjusted P<0.05) is shown. [Figure 16] The mean (± standard deviation) of plasma concentrations of MPA after administration of MMF alone (day 1) and in the presence of voclosporine (day 7) are shown. [Figure 17] The mean (± standard deviation) of MPAG plasma concentrations after administration of MMF alone (day 1) and in the presence of voclosporine (day 7) are shown. [Figure 18] This image shows MALDI-MSI imaging of one of the three CNIs in mouse kidneys after IV administration of cyclosporine (CsA), tacrolimus (TAC), or voclosporine (VCS). The mass-signal ratio is visualized as a color intensity map (m / z intensity) to provide spatial information about the detected molecule. [Figure 19-1] The structures of various boclosporine metabolites are shown. A shows the boclosporine metabolite IM4n. B shows the primary metabolite boclosporine metabolite IM9. [Figure 19-2] The structures of various boclosporine metabolites are shown. C represents the boclosporine metabolite IM1c(R). D represents the boclosporine metabolite IM1c(S). [Figure 19-3] The structures of various boclosporine metabolites are shown. E shows the boclosporine metabolite IM19 (MeBmt: cyclized). F shows the boclosporine metabolite IM19. [Figure 19-4] The structures of various boclosporine metabolites are shown. G represents the boclosporine metabolite IM4. H represents the boclosporine metabolite IM1-diol-1. [Figure 19-5] The structures of various boclosporine metabolites are shown. I shows the boclosporine metabolite IM1-diol-2. J shows the boclosporine metabolite IM1-diol-3, which is a diastereomer of IM1-diol-2 with a different configuration at the 1-η carbon of amino acid-1 (aa-1). [Figure 19-6]The structure of boclosporine metabolites is shown. K represents a hypothetical trihydroxylated boclosporine metabolite. [Figure 20] This image shows MALDI-MSI imaging of cyclosporine A ("CsA") or voclosporine ("VSP"), and their metabolites, in mouse kidneys after IV administration. The mass-signal ratio is visualized as a color intensity map (m / z intensity) to provide spatial information about the detected molecules. [Figure 21-1] The images show a series of in situ MALDI-MSI overlay and separate images of the parent drugs cyclosporine A ("CsA") or voclosporine ("VSP") and their metabolites in mouse kidneys after administration. A shows overlay images of cyclosporine A[CsA+Na]+ and voclosporine metabolite [VSP+Na]+ alongside separate images of each parent drug. B shows overlay and separate images of CsA metabolite [AM4n+Na]+ and VSP metabolite [IM4n+Na]+. C shows overlay and separate images of CsA metabolite [AM1 / AM1c / AM9+Na]+ and VSP metabolite [IM1c / IM4 / IM9+Na]+. The mass-signal ratio is visualized as a color intensity map (m / z intensity) to provide spatial information about the detected molecules. [Figure 21-2] The images show a series of in situ MALDI-MSI overlay and separate images of the parent drug cyclosporine A ("CsA") or voclosporine ("VSP") and its metabolites in mouse kidneys after administration. D shows the overlay and separate images for the CsA metabolite [AM19 / AM1c9+Na]+ and the VSP metabolite [IM19(cyclic)+Na]+. E shows the overlay and separate images for the CsA metabolite [AM19 / AM1c9+Na]+ and the VSP metabolite [IM1-diol-1 / IM19+Na]+. The mass-signal ratio is visualized as a color intensity map (m / z intensity) to provide spatial information about the detected molecules. [Figure 22A]This chart shows the viability of HEK293 cells plated on plastic laboratory equipment at different time points after treatment with various doses of CsA, Tac, or Vcs. Error bars indicate SEM results (n=6). *: p<0.05 compared to control (CTL). [Figure 22B] This shows the viability of HEK293 cells plated on glass or plastic laboratory equipment after treatment with various doses of CsA, Tac, or Vcs. Error bars indicate SEM results (n=3). [Figure 22C] This shows inhibition of calcineurin phosphatase activity in HEK293 cells treated with different doses of CsA, Tac, or Vcs. Error bars indicate SEM (n=6). *: p<0.05 compared to control. [Figure 22D] This study compares the expression of calcineurin isoforms in wild-type (WT) HEK293 cell lines with those of calcineurin α-isoform PPP3CA KO (αKO) and calcineurin beta-isoform PPP3CB KO (βKO). Anti-PPP3CA and anti-PPP3CB antibodies specific to the α and β isoforms, respectively, were used for detection. β-actin and GAPDH were used as loading controls. [Figure 22E] This chart shows the relative calcineurin protein expression in WT, αKO, or βKO HEK293 cell lines. Error bars indicate SEM (n=3). *: p<0.05 compared to WT control. [Figure 22F] This shows the inhibition of calcineurin phosphatase activity in WT, αKO, or βKO HEK293 cell lines treated with various concentrations of CsA, Tac, or Vcs. Error bars indicate SEM (n=5). *: p<0.05 compared to control. ^: p<0.05 compared to WT control. [Figure 22G] Western blots for MMP-9 and Smad1, downstream targets of calcineurin, are shown in WT, αKO, or βKO HEK293 cell lines treated with 20 μM CsA, Tac, or Vcs. [Figure 22H] This shows the quantification of downstream target protein expression of MMP-9 and Smad1 in WT, αKO, or βKO HEK293 cell lines treated with 20 μM CsA, Tac, or Vcs. Error bars indicate SEM results (n=2). [Modes for carrying out the invention]

[0093] This specification provides methods for treatment, methods for selecting subjects for treatment, and uses such as the therapeutic use of voclosporine, including selecting subjects who have previously received different calcineurin inhibitors (CNIs), such as cyclosporine or tacrolimus or derivatives thereof, as immunosuppressants. In some embodiments, the methods and uses described herein also include administering voclosporine to the selected subjects. In some embodiments, voclosporine is administered to the selected subjects.

[0094] Conventional CNIs, such as cyclosporine (including cyclosporine derivatives such as cyclosporine A (CsA)) and tacrolimus (TAC), or their derivatives, are potent immunosuppressants and have been tested for the treatment of various conditions that commonly require long-term immunosuppression, including in combination with organ or tissue transplantation. Conventional CNI compounds have been associated with adverse effects, side effects, or toxicity, such as drug-induced nephrotoxicity, in some situations. There is a need for CNIs that have a low or very low risk of adverse effects or toxicity and are tolerable for long periods or can be used for long-term administration. In some embodiments, subjects who have previously received conventional CNIs, particularly for long periods, are at risk of adverse effects or toxicity, or have already expressed one or more indicators of adverse effects or toxicity.

[0095] In some embodiments, a subject who has previously received a first CNI is selected for administration of voclosporine in the use of the provided method, protocol, treatment regimen and / or therapeutic use. In some embodiments, the provided embodiments include switching the use of a conventional CNI (e.g., cyclosporine, tacrolimus, or derivatives thereof; hereafter referred to in some embodiments as “conventional CNI,” “first-generation CNI,” or “first CNI”) as an immunosuppressant to voclosporine. In some embodiments, the provided embodiments enable the long-term use of a CNI (voclosporine) while avoiding drug-induced nephrotoxicity and other clinical problems, for example, in the treatment of proteinuric kidney diseases such as lupus nephritis (LN) or in connection with transplantation. In some embodiments, the CNI administered to the selected subject is voclosporine. In some embodiments, the provided embodiments are based on the observation that voclosporine, unlike cyclosporine or tacrolimus, does not require therapeutic drug monitoring. In some embodiments, the disclosure includes switching from conventional CNI administration to voclosporine in subjects requiring long-term CNI administration and who are highly susceptible to or at increased risk of acute or chronic drug-induced nephrotoxicity or other adverse effects from CNI administration. In some embodiments, the individual requires immunosuppressive therapy and presents with one or more risk factors for the development of calcineurin inhibitor-induced nephrotoxicity.

[0096] In some embodiments, the methods and uses provided are based on observations that treatment with voclosporine in subjects requiring CNI therapy, such as those with lupus nephritis, or those who have undergone or are candidates for organ or tissue transplantation, provides safe and effective treatment without substantially increasing susceptibility to or risk of drug-induced nephrotoxicity or the occurrence of many of the clinical problems associated with conventional CNI. In clinical trials, voclosporine has been shown to have higher 3-year remission and response rates compared to standard treatment while maintaining renal function, and without the clinical symptoms of toxicity shown in conventional CNI. In some embodiments, the results provided herein support that treatment with voclosporine as an immunosuppressant has no substantial effect on certain drug-induced adverse effects or toxicities that may be associated with conventional CNI, such as the concentration of urinary electrolytes and / or lipids in the subjects. In some embodiments, as described herein, the use of conventional CNIs may be associated with adverse or toxic tubular dysfunction, electrolyte effects such as hypomagnesemia and hyperkalemia, dyslipidemia, increased inflammatory lipids, drug interactions, and glucose dysregulation such as hyperglycemia or new-onset diabetes, whereas voclosporine does not exhibit such adverse or toxic effects, or exhibits a reduction in such adverse or toxic effects.

[0097] The methods and uses provided are also based on observations from imaging studies, for example, that in the kidney, conventional CNIs such as cyclosporine or tacrolimus and their metabolites accumulate at high concentrations, particularly in the cortex, whereas voclosporine and its metabolites do not accumulate at high concentrations. In some embodiments, the results provided herein support that treatment with voclosporine does not result in the development of glucose dysregulation and diabetes associated with conventional CNIs. In some embodiments, the results provided herein support that treatment with voclosporine is associated with a favorable metabolic profile with respect to lipids and glucose.

[0098] In some embodiments, voclosporine has also been observed to reduce drug interactions with other drugs or immunosuppressants commonly administered with CNI, such as mycophenolate mofetil (MMF) or its active component mycophenolate (MPA). In some embodiments, co-administration with cyclosporine A (CsA) is associated with a decrease in blood MPA levels, and discontinuation of CsA results in MPA-related side effects such as leukopenia. In contrast, voclosporine has been observed to have no clinically significant effect on blood MPA levels.

[0099] Furthermore, voclosporine has the advantage of having a high affinity for calcineurin. Voclosporine can also be distributed to organs such as the lungs at higher concentrations than in the blood, and is found at high concentrations in red blood cells.

[0100] As further described herein, voclosporine offers several advantages over conventional CNIs, particularly in subjects treated with conventional CNIs such as cyclosporine or tacrolimus. The results described herein support the use or switching to voclosporine, as well as the methods, treatment regimens, protocols, and benefits of use provided herein, for subjects requiring CNI therapy, especially those receiving conventional CNIs and at risk of drug-induced adverse effects or toxicity, or exhibiting one or more indicators thereof.

[0101] In some aspects, these results support the benefits of switching subjects from conventional CNIs such as cyclosporine or tacrolimus to voclosporine, particularly for long-term immunosuppression. These benefits include avoiding wasted medication and unnecessary exposure to potential side effects of immunosuppressant therapy. Since immunosuppressant treatment regimens are typically long-term, and many immunosuppressants have undesirable side effects, such benefits are especially important for subjects at risk of adverse effects or toxicity. Therefore, voclosporine can be administered to these subjects for much longer periods compared to conventional or traditional CNIs. Voclosporine has also been observed to have remarkably high drug persistence. Approximately 24 months after the approval of voclosporine for the treatment of lupus nephritis (LN), estimates based on patient databases showed that approximately 26% of subjects were continuing voclosporine treatment, which was significantly higher than expected. These observations support the possibility of using voclosporine as a long-term immunosuppressant in place of conventional or traditional CNIs. Patients who have previously undergone conventional or traditional CNI therapy will likely benefit in many ways from the use of voclosporine as an immunosuppressant.

[0102] All publications referenced herein, including patent documents, scientific articles, and databases, are incorporated by reference as a whole for all purposes, to the same extent that each individual publication is incorporated by reference individually. If any definitions contained herein conflict with or contradict any definitions contained herein by reference in any patent, application, publication, or other publication incorporated herein by reference, the definitions contained herein shall prevail.

[0103] The section headings used in this specification are for organizational purposes only and should not be construed as limiting the subjects described.

[0104] I. Treatment methods and use of voclosporine This specification provides a method and use of treatment comprising selecting a subject that has been previously administered a first CNI, which is a conventional calcineurin inhibitor (CNI), such as cyclosporine, tacrolimus, or a derivative thereof, and administering voclosporine to the subject. In some embodiments, the use of voclosporine or a composition comprising voclosporine, according to any of the methods described herein, is also provided. The use includes the use of voclosporine in such methods and treatments, and in the preparation of agents for carrying out such methods. In some embodiments, the method is carried out by selecting a subject that has been previously administered a first CNI, such as cyclosporine, tacrolimus, or a derivative thereof, and administering voclosporine to the selected subject. In some embodiments, the subject has previously received a first CNI for immunosuppression for at least 30 days. In some embodiments, a subject exhibits one or more indicators of adverse effects or toxicity associated with the first CNI, such as drug-induced nephrotoxicity, drug-induced hypercalcemia, drug-induced dyslipidemia, new-onset diabetes, or drug interactions with other immunosuppressants, after having previously received the first CNI. In some embodiments, the method and use provided comprises administering an effective dose of voclosporine to a subject who has previously been administered the first CNI for immunosuppressive purposes.

[0105] In some embodiments, the treatment method includes selecting a subject who has previously received a first CNI, such as cyclosporine, tacrolimus, or derivatives thereof, for administration of voclosporine. In some embodiments, the method includes discontinuing the administration of cyclosporine, tacrolimus, or derivatives thereof. In some embodiments, the method includes administering a therapeutically effective dose of voclosporine to a selected subject who has previously received a first CNI, such as cyclosporine, tacrolimus, or derivatives thereof, for immunosuppression. In some embodiments, the provided embodiments include selecting a subject who exhibits one or more indicators of drug-induced toxicity or adverse effects due to prior administration of the first CNI. In some embodiments, the selection of a subject for administration of voclosporine is based on any of the criteria or assays described herein, for example, in Section II. In some embodiments, the subject is selected for voclosporine based on a renal biopsy.

[0106] In some embodiments, a subject who has previously been administered a first CNI (such as cyclosporine or tacrolimus) is selected, the administration of the first CNI is discontinued, and the subject is administered voclosporine. In some embodiments, voclosporine is administered based on any of the methods or treatment regimens described herein, for example, in Section III.

[0107] A. Immunosuppression by the first calcineurin inhibitor (CNI). In some embodiments, subjects treated according to the methods and uses provided herein include subjects requiring immunosuppression. In some embodiments, subjects are receiving immunosuppressive agents, such as conventional CNIs, such as cyclosporine, tacrolimus, or derivatives thereof, for example, over a long period of time. Often, immunosuppressants need to be administered over a long period of time, for example, due to autoimmune diseases or as a result of organ or tissue transplantation. In some embodiments, subjects require immunosuppression, for example, the subject is an organ transplant recipient, an organ transplant candidate, has a condition related to transplant rejection, or has an autoimmune disease.

[0108] In some embodiments, the provided method and use comprises selecting a subject that has previously received a first CNI and administering voclosporine to the selected subject. In some embodiments, the subject has previously received a conventional CNI, such as cyclosporine, tacrolimus, or a derivative thereof, as an immunosuppressant before being selected for administration of voclosporine. In some embodiments, the first CNI is a conventional CNI, a first-generation CNI, or a conventional CNI.

[0109] In some embodiments, subjects treated according to the methods and uses provided herein include, for example, subjects requiring immunosuppression due to the risk of transplant rejection. In some embodiments, subjects are candidates for transplantation, such as organ transplantation, tissue transplantation, or cell transplantation. In some embodiments, subjects have previously received heart, lung, liver, kidney, pancreas, skin, intestine, or corneal transplantation. In some embodiments, subjects are candidates for heart, lung, liver, kidney, pancreas, skin, intestine, or corneal transplantation. In some embodiments, subjects are candidates for transplantation, such as organ transplantation, tissue transplantation, or cell transplantation, and subjects require immunosuppression. In some embodiments, subjects are kidney transplant recipients (KTRs). In some embodiments, subjects are candidates for kidney transplantation.

[0110] In some embodiments, the subject has a condition related to transplant rejection. In some embodiments, the condition is related to rejection of heart, lung, liver, kidney, pancreas, skin, intestine, or cornea transplants. In some embodiments, the condition is related to heart transplant rejection. In some embodiments, the condition is related to lung transplant rejection. In some embodiments, the condition is related to liver transplant rejection. In some embodiments, the condition is related to kidney transplant rejection. In some embodiments, the condition is related to pancreas transplant rejection. In some embodiments, the condition is related to skin transplant rejection. In some embodiments, the condition is related to intestine transplant rejection. In some embodiments, the condition is related to corneal transplant rejection.

[0111] In some embodiments, the subject has received immunosuppressant therapy related to transplantation, such as a first CNI, which may be a conventional CNI such as cyclosporine, tacrolimus, or a derivative thereof. In some embodiments, the subject receives a first CNI in connection with transplantation during a treatment period with the first CNI, which may be initiated before or after transplantation. In some embodiments, the subject receives a first CNI during a treatment period with the first CNI, which may be initiated before transplantation and terminated after transplantation. In some embodiments, the subject receives a first CNI during a treatment period with the first CNI, which may be initiated after transplantation and terminated after transplantation.

[0112] In some embodiments, the subjects have an autoimmune disease. Examples of autoimmune diseases include, but are not limited to, autoimmune blood disorders (e.g., hemolytic anemia, aplastic anemia, pure red cell aplasia and idiopathic thrombocytopenia), systemic lupus erythematosus (SLE), lupus nephritis (LN), polychondritis, sclerosis, ANCA vasculitis, dermatomyositis, chronic active hepatitis, myasthenia gravis, psoriasis, Stevens-Johnson syndrome, idiopathic sprue, and (autoimmune) inflammatory bowel disease (e.g., ulcers). Examples include juvenile colitis and Crohn's disease, endocrine eye disorders, Graves' disease, sarcoidosis, multiple sclerosis, primary biliary cirrhosis, juvenile diabetes mellitus (type 1 diabetes mellitus), uveitis (anterior and posterior), keratoconjunctivitis sicca and vernal keratoconjunctivitis, interstitial pulmonary fibrosis, psoriatic arthritis, glomerulonephritis (with and without nephrotic syndrome, including idiopathic nephrotic syndrome or minimal change nephrotic syndrome), and juvenile dermatomyositis. In some embodiments, subjects have or are at risk of systemic lupus erythematosus (SLE). In some embodiments, subjects have or are at risk of lupus nephritis (LN).

[0113] In some embodiments, the subjects require long-term administration of immunosuppressants. In some embodiments, immunosuppressants such as CNI require long-term administration. For example, certain treatment guidelines for diseases such as lupus nephritis published by medical and scientific societies recommend administering immunosuppressants for at least 6 months as "induction" therapy, and administration as "maintenance" therapy may be expected to continue for more than 3 years (see, for example, “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 embodiments, the subjects require administration of immunosuppressants for at least 1 month, at least 3 months, at least 6 months, at least 1 year, or longer, for example, more than 5 years.

[0114] In some embodiments, the method and use of the present invention includes selecting a subject who has previously received a first CNI, which is a “conventional CNI” (also referred to in some cases as a “conventional CNI” or “first-generation CNI,” such as cyclosporine, tacrolimus, or derivatives thereof). In some embodiments, the method includes selecting a subject who exhibits one or more indicators of adverse effects, side effects, or toxicity associated with the first CNI, such as drug-induced nephrotoxicity, new-onset diabetes mellitus, drug-induced dyslipidemia, or drug-drug interactions with other drugs used in combination. In some embodiments, the subject is selected based on one or more criteria associated with one or more indicators. In some embodiments, the method and use of the present invention includes discontinuing the administration of the first CNI to the selected subject and administering voclosporine. In some embodiments, methods and uses related to the treatment or reduction of drug-induced nephrotoxicity, drug-induced tubular dysfunction, drug-induced hypercalcemia, new-onset diabetes mellitus, drug-induced dyslipidemia, and the reduction of chronic drug-induced nephrotoxicity are also provided. Furthermore, uses such as the therapeutic use of voclosporine in accordance with one of the methods provided are also offered.

[0115] In some embodiments, subjects include those who have received a first CNI, which is a conventional CNI such as cyclosporine, tacrolimus, or a derivative thereof. In some embodiments, subjects require immunosuppression, such as long-term or sustained immunosuppression for at least several months or several years. In some embodiments, the first CNI is administered for immunosuppression to treat a disease or condition, such as an autoimmune disease including systemic lupus erythematosus (SLE), lupus nephritis (LN), or psoriasis, or to subjects who have received or are candidates for organ or tissue transplantation.

[0116] CNIs are used as immunosuppressants for a variety of conditions, particularly those involving autoimmune elements in their pathology. The immunosuppressive activity of CNIs is thought to help treat the direct causes of symptoms in conditions related to immune system activity. For example, CNIs are used alone or in combination with other drugs as part of transplantation therapy, particularly in patients undergoing kidney, liver, and heart transplants, to prevent transplant rejection. CNIs are also used alone or in combination with methotrexate to treat rheumatoid arthritis or psoriasis. CNIs are also used to treat lupus nephritis.

[0117] The immunosuppressive properties of CNIs such as cyclosporine and tacrolimus are thought to be brought about by the inhibition of calcineurin, a phosphatase. Calcineurin is an important enzyme involved in the activation and proliferation of T cells. Cyclosporine and tacrolimus are thought to inhibit the phosphatase activity of calcineurin. This inhibition suppresses IL-2 production, and therefore suppresses T cell activation. Many immunosuppressants, including CNIs, need to be administered for at least one month, at least three months, at least six months, at least one year, or for longer periods, such as more than five years.

[0118] In some embodiments, the first CNI is cyclosporine or a derivative thereof. In some embodiments, the conventional CNI is cyclosporine or a derivative thereof. In some embodiments, the conventional CNI is cyclosporine. In some embodiments, the conventional CNI is cyclosporine A (CsA). Cyclosporine (sometimes also called cyclosporine or ciclosporin) and derivatives of cyclosporine such as cyclosporine A (CsA) have remained the first-line CNI used for transplant-related immunosuppression. Although cyclosporine A and voclosporine are structurally similar, these two compounds exhibit 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 embodiments, subjects are selected for voclosporine administration if they have previously received cyclosporine or a derivative thereof for immunosuppression. In some embodiments, subjects are selected for voclosporine administration if they have previously received cyclosporine A (CsA) for immunosuppression.

[0119] In some embodiments, the first CNI is tacrolimus (TAC). In some embodiments, the conventional CNI is tacrolimus (TAC) or a derivative thereof. In some embodiments, the conventional CNI is tacrolimus. Tacrolimus has also been successfully used for transplant-related immunosuppression. Both cyclosporine and tacrolimus were first introduced for parenchymal organ transplantation in the 1980s and are considered conventional CNIs or conventional first-generation CNIs. Currently, the majority of KTRs have CNI-based regimens that prefer tacrolimus over cyclosporine (including derivatives such as cyclosporine A (CsA)) as standard maintenance immunosuppression. This is because tacrolimus is superior in long-term kidney 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 embodiments, subjects are selected for voclosporine administration if they have previously received tacrolimus or its derivatives for immunosuppression.

[0120] B. Harmful effects or toxicity Unfortunately, long-term administration of conventional CNIs can lead to adverse effects or toxicity. For example, in patients with glomerulonephropathy (e.g., lupus nephritis), administration of conventional CNIs can lead to further acute or chronic drug-induced nephrotoxicity. Long-term use of conventional CNIs such as cyclosporine, tacrolimus, or their derivatives has been reported to cause renal failure, including reversible decline in GFR (now recognized as acute CNI nephrotoxicity), as well as irreversible and progressive tubulointerstitial damage and glomerulosclerosis or irreversible renal impairment as a result of chronic CNI nephrotoxicity. In general, patients who present with or are prone to acute or chronic drug-induced nephrotoxicity associated with conventional CNIs, particularly those with glomerulonephropathy (e.g., autoimmune glomerulonephropathy), or other clinical problems, may benefit from switching to a different CNI, namely voclosporine. This specification shows that voclosporine exhibits very low or low levels of adverse effects or toxicity, such as nephrotoxicity, compared to conventional CNIs.

[0121] In some embodiments, conventional CNI (i.e., conventional CNI or first-generation CNI) has been reported to be associated with acute kidney injury (hemodynamic and mostly reversible after dose reduction) or chronic progressive kidney disease (typically irreversible). Other effects of conventional CNI on the kidney include tubular dysfunction and thrombotic microangiopathy, which can lead to acute renal allograft loss. In some embodiments, conventional CNI has been reported to present with irreversible histopathological renal injury characterized by arteriolar hyalinization, interstitial fibrosis, tubulointerstitial injury, tubular atrophy, or glomerulosclerosis.

[0122] In some embodiments, the subjects selected for treatment with voclosporine exhibit one or more indicators, such as one or more clinical symptoms of toxicity or adverse effects of a first CNI. In some embodiments, the first CNI is a conventional CNI such as cyclosporine and tacrolimus.

[0123] In some embodiments, conventional CNIs such as cyclosporine or tacrolimus have been shown to contribute to glucose dysregulation, hyperkalemia, hypomagnesemia, drug interactions (DDIs), and increased serum lipids, including inflammatory lipids.

[0124] In some embodiments, if a subject has previously received a first CNI for immunosuppression, the subject is selected according to the methods and uses described herein. In some embodiments, if a subject has previously received cyclosporine or a derivative thereof for immunosuppression, the subject is selected according to the methods and uses described herein. In some embodiments, if a subject has previously received tacrolimus or a derivative thereof for immunosuppression, the subject is selected according to the methods and uses described herein. In some embodiments, the methods and uses provided include selecting a subject that exhibits one or more indicators of adverse effects or toxicity associated with long-term conventional CNI, such as drug-induced nephrotoxicity, drug-induced hypercalcemia, drug-induced dyslipidemia, new-onset diabetes, or drug-drug interactions with other immunosuppressants. In some embodiments, if a subject has previously received a first CNI for immunosuppression and exhibits one or more indicators of adverse events or toxicity, such as drug-induced nephrotoxicity, after receiving the first CNI, the subject is selected according to the methods and uses described herein. Examples of indicators that may be used to assess the presence of adverse effects and toxicity associated with the first CNI are, for example, those described herein in sections IB, IC, and II.

[0125] C. Methods for treating or reducing adverse effects or toxicity A method of treatment is provided, including the administration of voclosporine. In some embodiments, a method is provided for treating or mitigating adverse effects or toxicity associated with the administration of a conventional CNI, for example, long-term administration of a conventional CNI. In some embodiments, the method and use provided includes selecting a subject who has been administered a first CNI, such as cyclosporine, tacrolimus, or a derivative thereof, and who may exhibit one or more indicators of adverse effects or toxicity associated with the first CNI. In some embodiments, the embodiment provided includes the administration of voclosporine to the selected subject. In some embodiments, the embodiment provided includes administering voclosporine, which has been observed to be associated with benefits such as low or very low toxicity or adverse effects, to the subject exhibiting one or more indicators of adverse effects or toxicity associated with the first CNI. In some embodiments, the method and use provided can treat, prevent, or mitigate adverse effects or toxicity associated with the administration of a conventional CNI. In some embodiments, the CNI administered to the subject is switched from a conventional CNI to voclosporine. In some embodiments, the methods and uses described herein may be used to treat or mitigate adverse effects or toxicity that may be associated with the administration of conventional CNIs, such as drug-induced nephrotoxicity, drug-induced hypercalcemia, drug-induced dyslipidemia, new-onset diabetes, or drug interactions with other immunosuppressants.

[0126] This specification provides methods for mitigating chronic drug-induced nephrotoxicity. In some embodiments, the treatment method comprises selecting a subject exhibiting symptoms of chronic drug-induced nephrotoxicity who has previously received a first CNI, such as cyclosporine, tacrolimus, or a derivative thereof, for administration of voclosporine. In some embodiments, the selected subject is subsequently administered voclosporine. In some embodiments, the method comprises discontinuing the administration of the first CNI. In some embodiments, the method comprises administering a therapeutically effective dose of voclosporine to the selected subject who has previously received a first CNI for immunosuppression.

[0127] In some embodiments, voclosporine therapy can reduce, prevent, improve, or reverse drug-induced nephrotoxicity, such as chronic or acute drug-induced nephrotoxicity. In some embodiments, any of the methods, protocols, and uses provided herein may be used for therapeutic purposes in subjects requiring immunosuppression with CNI and who may be susceptible to or at increased risk of drug-induced nephrotoxicity. In some embodiments, any of the subjects described herein, such as those requiring immunosuppression with CNI and who may be susceptible to or at increased risk of drug-induced nephrotoxicity, may be administered voclosporine according to any of the methods, protocols, and uses provided herein. In some embodiments, a method is provided for treating drug-induced nephrotoxicity that may be associated with a first CNI, by administering voclosporine to a subject who has previously received a first CNI for immunosuppression for at least 30 days, wherein the first CNI is a first CNI.

[0128] In some embodiments, subjects exhibiting one of the following indicators—acute arteriolar disease, tubular vacuolation, and thrombotic microangiopathy (TMA)—may have or be at risk of acute drug-induced nephrotoxicity. In some embodiments, subjects exhibiting one of the following indicators—interstitial fibrosis and tubular atrophy, arteriolar medial hyalinization, glomerular capsular fibrosis, whole-segmental glomerulosclerosis, focal segmental glomerulosclerosis (FSGS), juxtaglomerular apparatus hyperplasia, and tubular microcalcification—may have or be at risk of chronic drug-induced nephrotoxicity. In some embodiments, subjects are selected for treatment if they exhibit one or more of the indicators described herein related to drug-induced nephrotoxicity or other adverse effects or toxicities related to conventional CNI.

[0129] In some embodiments, subjects who have received or are candidates for organ or tissue transplantation and conventional CNIs as immunosuppressants to reduce or prevent transplant rejection, for example, may have or be at risk of acute drug-induced nephrotoxicity. In some embodiments, subjects may have received or are candidates for kidney, liver, or heart transplantation. In some embodiments, subjects may have received or are candidates for kidney transplantation.

[0130] Other adverse effects associated with conventional CNIs include dyslipidemia, which may contribute to an increased risk of cardiovascular disease. In some aspects, dyslipidemia may be associated with inflammation and the use of immunosuppressants such as CNIs.

[0131] In some embodiments, one or more indicators of drug-induced nephrotoxicity include, for example, renal dysfunction such as changes in renal hemodynamics caused by other therapeutic compounds; osmotic nephrotic syndrome caused by common pharmaceutical excipients such as mannitol, glucose, sucrose, and dextran, or by radiographic contrast agents; recurrent disease (primary HUS / TTP), ischemia-reperfusion injury, renal infections, and side effects of various other drugs such as mTOR inhibitors and antivirals.

[0132] This specification provides methods for alleviating or treating drug-induced hypercalcemia. In some embodiments, the treatment method comprises selecting a subject exhibiting symptoms of drug-induced hypercalcemia who has previously received a first CNI for immunosuppression for administration of voclosporine. In some embodiments, the method comprises discontinuing the administration of the first CNI. In some embodiments, the method comprises administering a therapeutically effective dose of voclosporine to the selected subject who has previously received a first CNI for immunosuppression.

[0133] In some embodiments, the method includes evaluating the calcium fraction excretion rate in subjects who have previously received a first CNI for immunosuppression. In some embodiments, the method includes selecting subjects who show an increase of more than 10% in calcium fraction excretion rate compared to the calcium fraction excretion rate of the same subjects before receiving the first CNI for immunosuppression.

[0134] In some embodiments, treatment with voclosporine can reduce, prevent, improve, or mitigate drug-induced hypercalcemia. In some embodiments, any of the methods, protocols, and uses provided herein may be used for therapeutic purposes in subjects requiring immunosuppression with CNI and who may be susceptible to or at increased risk of drug-induced hypercalcemia. In some embodiments, any of the subjects described herein, such as those requiring immunosuppression with CNI and who may be susceptible to or at increased risk of drug-induced hypercalcemia, may be selected for administration of voclosporine according to any of the methods, protocols, and uses provided herein.

[0135] This specification provides methods for alleviating or treating new-onset diabetes. In some embodiments, the treatment method comprises selecting a subject exhibiting one or more symptoms of new-onset diabetes who has previously received a first CNI for immunosuppression for administration of voclosporine. In some embodiments, the method comprises discontinuing the administration of the first CNI. In some embodiments, the method comprises administering a therapeutically effective dose of voclosporine to the selected subject who has previously received a first CNI for immunosuppression.

[0136] In some embodiments, treatment with voclosporine can reduce, prevent, improve, or reverse new-onset diabetes. In some embodiments, any of the methods, protocols, and uses provided herein may be used for therapeutic purposes in subjects requiring immunosuppression with CNI and who may be susceptible to new-onset diabetes or who may exhibit an increased risk or susceptibility thereto. In some embodiments, any of the subjects described herein, for example, subjects requiring immunosuppression with CNI and who may be susceptible to new-onset diabetes or who may exhibit an increased risk or susceptibility thereto, may be selected for administration of voclosporine according to any of the methods, protocols, and uses provided herein.

[0137] This specification provides methods for alleviating or treating drug-induced dyslipidemia. In some embodiments, the treatment method comprises selecting a subject exhibiting symptoms of drug-induced dyslipidemia who has previously received a first CNI for immunosuppression for administration of voclosporine. In some embodiments, the method comprises discontinuing the administration of the first CNI. In some embodiments, the method comprises administering a therapeutically effective dose of voclosporine to the selected subject who has previously received a first CNI for immunosuppression.

[0138] In some embodiments, treatment with voclosporine can reduce, prevent, improve, or mitigate drug-induced dyslipidemia. In some embodiments, any of the methods, protocols, and uses provided herein may be used for therapeutic purposes in subjects requiring immunosuppression with CNI and who may be susceptible to or at increased risk of drug-induced dyslipidemia. In some embodiments, any of the subjects described herein, such as subjects requiring immunosuppression with CNI and who may be susceptible to or at increased risk of drug-induced dyslipidemia, may be selected for administration of voclosporine according to any of the methods, protocols, and uses provided herein.

[0139] This specification provides methods for alleviating or treating drug-induced dyslipidemia. In some embodiments, the treatment method comprises selecting a subject exhibiting symptoms of drug-induced dyslipidemia who has previously received a first CNI for immunosuppression for administration of voclosporine. In some embodiments, the method comprises discontinuing the administration of the first CNI. In some embodiments, the method comprises administering a therapeutically effective dose of voclosporine to the selected subject who has previously received a first CNI for immunosuppression.

[0140] In some embodiments, treatment with voclosporine can reduce, prevent, improve, or mitigate drug-induced dyslipidemia. In some embodiments, any of the methods, protocols, and uses provided herein may be used for therapeutic purposes in subjects requiring immunosuppression with CNI and who may be susceptible to or at increased risk of drug-induced dyslipidemia. In some embodiments, any of the subjects described herein, such as subjects requiring immunosuppression with CNI and who may be susceptible to or at increased risk of drug-induced dyslipidemia, may be selected for administration of voclosporine according to any of the methods, protocols, and uses provided herein.

[0141] This specification provides methods for preventing drug interactions with other immunosuppressants, for example, a decrease in blood levels of different immunosuppressants or their metabolites that may be used with CNIs. In some embodiments, conventional CNIs such as cyclosporine or tacrolimus may be associated with a decrease in blood levels of mycophenolate (MPA) when conventional CNIs are used in combination with mycophenolate mofetil (MMF) for immunosuppression. In some embodiments, the treatment method includes selecting a subject who has previously received a first CNI for immunosuppression and is exhibiting symptoms of a drug interaction for administration of voclosporine. In some embodiments, the method includes discontinuing the administration of the first CNI. In some embodiments, the method includes administering a therapeutically effective dose of voclosporine to a selected subject who has previously received a first CNI for immunosuppression.

[0142] In some embodiments, treatment with voclosporine can reduce, prevent, improve, or mitigate drug interactions, for example, by preventing a decrease in the blood levels of different immunosuppressants that may be used with CNIs, such as mycophenolate mofetil (MMF) or its metabolite, mycophenolate (MPA). In some embodiments, any of the methods, protocols, and uses provided herein may be used for therapeutic purposes in subjects who require immunosuppression with CNIs and who may be susceptible to or at increased risk of drug interactions. In some embodiments, any of the subjects described herein, such as those who require immunosuppression with CNIs and who may be susceptible to or at increased risk of drug interactions, may be selected for administration of voclosporine according to any of the methods, protocols, and uses provided herein.

[0143] In some cases, various clinical risk factors exist for the development of drug-induced nephrotoxicity. Typical diagnoses of susceptibility to chronic drug-induced nephrotoxicity include aging, ischemia-reperfusion injury, infections (UTIs, CMV), chronic ischemia, diabetes mellitus, hypertension, glomerular ischemia, bone and mineral imbalances, and proteinuria. In some cases, patients with risk factors for drug-induced nephrotoxicity from prior administration of a first CNI are selected for voclosporine administration. In some embodiments, further risk factors include systemic overexposure to cyclosporine and tacrolimus, administration of mTOR inhibitors, presence of a specific ABCB1 genotype in the kidney, expression of ABCB1 protein in renal tubular epithelial cells, presence of a CYP3A4 / 5 genotype, expression of CYP3A4 / 5 protein in renal tubular epithelial cells, interaction with other drugs that alter CNI metabolites (e.g., ketoconazole), advanced renal 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.

[0144] II. Identification and Selection of Targets In some embodiments, the methods and uses provided include administering voclosporine to a selected subject.

[0145] In some embodiments, if a subject has previously received a conventional calcineurin inhibitor (CNI) (such as cyclosporine, tacrolimus, or derivatives thereof) as a first CNI for a period longer than a specific duration, such as more than 30 days, the subject is selected for voclosporine administration.

[0146] In some embodiments, a subject is selected for administration of voclosporine if the subject has previously received a conventional CNI (such as cyclosporine, tacrolimus, or derivatives thereof) and exhibits one or more indicators of adverse effects or toxicity that may be related to the first CNI, such as drug-induced nephrotoxicity, drug-induced hypercalcemia, drug-induced dyslipidemia, new-onset diabetes, or drug-drug interactions with other immunosuppressants.

[0147] In some embodiments, the methods and uses provided include investigating or evaluating one or more indicators of adverse effects or toxicity that may be associated with a conventional CNI. In some embodiments, the methods and uses provided include investigating or evaluating one or more indicators of adverse effects or toxicity that may be associated with cyclosporine. In some embodiments, the methods and uses provided include investigating or evaluating one or more indicators of adverse effects or toxicity that may be associated with tacrolimus. In some embodiments, the methods and uses provided include investigating or evaluating one or more indicators of adverse effects or toxicity after a subject has initiated administration of a conventional CNI as a first CNI, and comparing this to the level of the same indicator measured at baseline, i.e., before administration of the first CNI. In some embodiments, “baseline level” or “baseline measurement” means the level of one or more indicators measured or evaluated in a subject before receiving a first CNI such as cyclosporine, tacrolimus, or a derivative thereof.

[0148] In some embodiments, one or more indicators of adverse effects or toxicity may be investigated based on methods and assays for evaluating and monitoring such adverse effects and toxicity as described herein. In some embodiments, the methods and uses herein include evaluating one or more indicators of adverse effects or toxicity, such as drug-induced nephrotoxicity, and selecting subjects based on specific criteria or thresholds for specific indicators indicating that an adverse effect or toxicity is present or at risk. In some embodiments, subjects are selected based on criteria or thresholds for one or more indicators related to adverse effects or toxicity, and voclosporine is administered to the selected subjects. In some embodiments, administration of a first CNI is discontinued before initiation of voclosporine administration. In some embodiments, in the selected subjects, the CNI used for immunosuppression is switched from a conventional CNI (such as cyclosporine, tacrolimus, or derivatives thereof) to voclosporine.

[0149] In some embodiments, the methods and uses provided include evaluating a subject's response to treatment, or aspects related to treatment, to identify subjects for switching from conventional calcineurin inhibitors to voclosporine. In some embodiments, the methods and uses provided include evaluating specific aspects of treatment or response, including, but not limited to, evaluating or monitoring renal function, renal biopsy, tubular dysfunction, biomarkers, lipid profiles, drug interactions, or glucose dysregulation.

[0150] A. Long-term administration of the first CNI In some embodiments, a method is provided for selecting subjects who have previously received a first CNI for immunosuppression for at least 30 days. In some embodiments, the first CNI is cyclosporine, tacrolimus, or a derivative thereof. In some embodiments, a subject has previously received the 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 embodiments, a subject has previously received cyclosporine, tacrolimus, or a derivative thereof for at least 2, 3, 4, 5, 6, 9, 12, 18, 24, 30, or 36 months. In some embodiments, if a subject has previously received the first CNI for at least 30 days, the subject is selected for voclosporine administration. In some embodiments, a subject is selected for voclosporine administration if the subject has previously received a first CNI for at least 60 days. In some embodiments, a subject is selected for voclosporine administration if the subject has previously received a first CNI for at least 90 days. In some embodiments, a subject is selected for voclosporine administration if the subject has previously received a first CNI for at least 120 days. In some embodiments, a subject is selected for voclosporine administration if the subject has previously received a first CNI for at least 150 days. In some embodiments, a subject is selected for voclosporine administration if the subject has previously received a first CNI for at least 180 days. In some embodiments, a subject is selected for voclosporine administration if the subject has previously received a first CNI for at least 1 year. In some embodiments, a subject is selected for voclosporine administration if the subject has previously received a first CNI for at least 1.5 years. In some embodiments, a subject is selected for voclosporine administration if the subject has previously received a first CNI for at least 2 years.In some embodiments, a subject is selected for voclosporine administration if the subject has previously received a first CNI for at least 2.5 years. In some embodiments, a subject is selected for voclosporine administration if the subject has previously received a first CNI for at least 3 years.

[0151] B. Renal function In some embodiments, the method or use herein further includes, or involves, assessing renal function in subjects, e.g., KTR subjects, or subjects involved in immunosuppression due to renal status (e.g., lupus nephritis (LN)) in order to identify subjects to switch from conventional CNI to voclosporine. In some embodiments, one or more indicators of drug-induced nephrotoxicity are assessed based on one or more renal biopsies.

[0152] In some embodiments, a subject is selected if, after receiving a first CNI, the subject has increased susceptibility to chronic drug-induced nephrotoxicity as assessed by a renal function study. In some embodiments, a subject is selected if the subject has increased susceptibility to drug-induced nephrotoxicity compared to a corresponding population. In some embodiments, a population of individuals means the entire affected population. In some embodiments, a population of individuals means the entire population of a particular sex. In some embodiments, a population of individuals means the entire population of a particular race. In some embodiments, a population of individuals means the entire population of a particular age group. In some embodiments, a population of individuals means the entire population of a particular geographical area. In some aspects, the provided embodiments include assessing or monitoring the risk of drug-induced nephrotoxicity by, for example, assessing or measuring changes in one or more of the indicators described herein, or one or more of the indicators described herein.

[0153] In some embodiments, one or more indicators of drug-induced nephrotoxicity include renal dysfunction, or an assessment or indicator related to or indicative of renal dysfunction. In some embodiments, a subject is selected if the subject exhibits renal dysfunction after receiving a first CNI. In some aspects, a subject having renal dysfunction is determined based on a calculated creatinine clearance by the Cockcroft-Gault formula of less than 60-90 mL / min (mild dysfunction), less than 30-60 mL / min (moderate dysfunction), or less than 15-30 mL / min (severe dysfunction), or a corresponding control subject (based on age and body mass index). In some embodiments, a subject is selected if the subject exhibits severe renal dysfunction (CL Cr ) of less than 30 mL / min after receiving a first CNI. In some embodiments, the subject exhibits severe renal dysfunction with a baseline eGFR, where the baseline eGFR is any one of about >30, >35, >40, >45, >50, >60, or >70 ml / min / 1.73m 2 . In some embodiments, tacrolimus C max and / or the AUC is increased in subjects with severe renal dysfunction compared to corresponding subjects without such dysfunction. In some embodiments, tacrolimus C max is increased in subjects with severe renal dysfunction by a factor of any one of about 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 compared to corresponding subjects without such dysfunction. In some embodiments, the tacrolimus AUC is increased in subjects with severe renal dysfunction by a factor of any one of about 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 compared to corresponding subjects without such dysfunction.

[0154] In some embodiments, one or more indicators of drug-induced nephrotoxicity include symptoms of renal disease, or assessments or indicators related to or indicating symptoms of renal disease. In some embodiments, subjects are selected if they exhibit one or more symptoms of renal disease after receiving a first CNI. In some embodiments, subjects have one or more types of renal disease, one or more of which contribute to increased susceptibility to chronic drug-induced nephrotoxicity. In some embodiments, subjects are selected if they have increased susceptibility to drug-induced nephrotoxicity and exhibit one or more forms of glomerulonephropathy. In some embodiments, subjects are selected if they have increased susceptibility to drug-induced nephrotoxicity, exhibit one or more forms of glomerulonephropathy, and long-term administration of conventional CNIs (such as cyclosporine or tacrolimus) may result in long-term renal injury, such as, but not limited to, further acute and chronic nephrotoxicity.

[0155] In some embodiments, one or more indicators of drug-induced nephrotoxicity include glomerulonephropathy, or an assessment or indicator associated with or indicating glomerulonephropathy. In some embodiments, the subjects represent glomerulonephropathy. In some embodiments, the subjects represent chronic glomerulonephropathy. In some embodiments, the subjects represent inflammatory glomerulonephropathy. In some embodiments, the subjects represent non-inflammatory glomerulonephropathy. In some embodiments, the subjects represent autoimmune glomerulonephropathy. In some embodiments, the subjects represent acute glomerulonephropathy. In some embodiments, the subjects represent glomerulonephritis. In some embodiments, the subjects represent chronic glomerulonephritis. In some embodiments, the subjects represent acute glomerulonephritis.

[0156] In some embodiments, the subjects exhibit inflammatory kidney disease. In some embodiments, the subjects exhibit non-inflammatory kidney disease. In some embodiments, the subjects exhibit inflammatory kidney disease in an autoimmune context. In some embodiments, autoimmune kidney disease may arise from autoantigens (e.g., Goodpasture antigen) within the kidney tissue. In some embodiments, autoimmune kidney disease may arise from autoantigens present outside the kidney causing immune complexes within the kidney and leading to tissue damage events (e.g., lupus nephritis). In some embodiments, autoimmune kidney disease may arise from antigens and / or antibodies, where these antigens and / or antibodies do not originate from or are not deposited within the kidney, but rather from the interaction of antibodies with the antigen or antigen-carrying cells (e.g., anti-neutrophil cytoplasmic antigen autoantibody (ANCA)-associated vasculitis or glomerulonephritis). In some embodiments, the subjects suffer from anti-glomerular basement membrane disease (anti-GBM disease). In some embodiments, the subjects suffer from lupus nephritis. In some embodiments, the subjects suffer from systemic lupus erythematosus (SLE). In some embodiments, up to half of subjects with systemic lupus erythematosus (SLE) may develop kidney nephritis (LN), which can lead to severe and permanent kidney damage, and in some cases, kidney failure. In some embodiments, subjects have ANCA-associated vasculitis. In some embodiments, subjects have ANCA-associated glomerulonephritis.

[0157] C. Renal tubular dysfunction In some embodiments, one or more indicators of drug-induced nephrotoxicity include tubular dysfunction, or an assessment or indicator related to or indicating tubular dysfunction. In some embodiments, subjects are selected based on an assessment of drug-induced tubular dysfunction and / or ionic homeostasis after receiving a first CNI. In some embodiments, the method includes selecting subjects based on an assessment of the level of one or more urinary electrolytes in a subject compared to baseline levels assessed before receiving a first CNI such as cyclosporine, tacrolimus, or a derivative thereof, and selecting subjects for voclosporine administration if the level of one or more urinary electrolytes is significantly lower or higher than a predetermined value compared to the baseline level. In some embodiments, the urinary electrolytes are selected from one or more of magnesium, sodium, and potassium.

[0158] In some embodiments, the urinary electrolyte is magnesium, and the range of the specified value is approximately 1 mg / dL to 40 mg / dL. In some embodiments, the urinary electrolyte is magnesium, and the specified value is approximately 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 embodiments, the urinary electrolyte is magnesium, and the range of the specified value is approximately 10 mg / dL to 30 mg / dL. In some embodiments, the urinary electrolyte is magnesium, and the specified value is approximately 20 mg / dL. In some embodiments, the urinary electrolyte is sodium, and the range of the specified value is approximately 5 mmol / L to 100 mmol / L. In some embodiments, the urinary electrolyte is sodium, and the predetermined value is approximately 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, or 100 mmol / L. In some embodiments, the urinary electrolyte is sodium, and the predetermined value range is approximately 30 mmol / L to 70 mmol / L. In some embodiments, the urinary electrolyte is sodium, and the predetermined value is approximately 50 mmol / L. In some embodiments, the urinary electrolyte is potassium, and the predetermined value range is approximately 1 mmol / L to 25 mmol / L. In some embodiments, the urinary electrolyte is potassium, and the predetermined value is approximately 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 embodiments, the urinary electrolyte is potassium, and the predetermined value range is approximately 5 mmol / L to 15 mmol / L. In some embodiments, the urinary electrolyte is potassium, and the predetermined value is approximately 10 mmol / L.

[0159] In some embodiments, one or more indicators of drug-induced nephrotoxicity include drug-induced hyperkalemia, hypomagnesemia, magnesium depletion, or hyperuricemia, or assessments or indicators associated with or indicating drug-induced hyperkalemia, hypomagnesemia, magnesium depletion, or hyperuricemia. In some embodiments, subjects are evaluated for drug-induced hyperkalemia, hypomagnesemia, magnesium depletion, or hyperuricemia after undergoing a first CNI and selected based on their presence. Hyperkalemia is assessed from collected serum samples and classified as mild (<5.1–6 mmol / l), moderate (<6–7 mmol / l), and severe (≥7 mmol / l). Low serum magnesium (hypomagnesemia) is determined as serum magnesium levels below the standard reference range, i.e., less than 1.4–1.8 mg / dL. Urine analysis showing magnesium excretion greater than 2 mEq (1 mmol or 24 mg) is classified as indicating renal magnesium depletion. High uric acid levels (hyperuricemia) are assessed from collected serum samples and are classified as values ​​exceeding the standard upper limit of 6.0–7.0 mg / dL.

[0160] In some embodiments, the method and use herein include evaluating the presence of serum and urine samples of subjects against baseline levels for hyperkalemia, hypomagnesemia, magnesium depletion, and hyperuricemia, and selecting subjects for voclosporine administration if hyperkalemia, hypomagnesemia, magnesium depletion, and hyperuricemia are detected.

[0161] In some embodiments, hyperkalemia is determined by a serum potassium level above one of approximately 4, 5, 6, 7, 8, 9, or 10 mmol / L. In some embodiments, hyperkalemia is determined by a serum potassium level above approximately 4 mmol / L. In some embodiments, hyperkalemia is determined by a serum potassium level above approximately 5 mmol / L. In some embodiments, hyperkalemia is determined by a serum potassium level above approximately 6 mmol / L. In some embodiments, hypomagnesemia is determined by a serum magnesium level below one of approximately 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 embodiments, hypomagnesemia is determined by a serum magnesium level below approximately 1.2 mg / dL. In some embodiments, hypomagnesemia is determined by a serum magnesium level below approximately 1.4 mg / dL. In some embodiments, hypomagnesemia is determined by a serum magnesium level of less than approximately 1.6 mg / dL. In some embodiments, magnesium depletion is determined by a urinary magnesium level greater than any one of approximately 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 embodiments, magnesium depletion is determined by a urinary magnesium level greater than approximately 1.0 mEq. In some embodiments, magnesium depletion is determined by a urinary magnesium level greater than approximately 2.0 mEq. In some embodiments, magnesium depletion is determined by a urinary magnesium level greater than approximately 3.0 mEq. In some embodiments, hyperuricemia is determined by a serum uric acid level exceeding one of the following: approximately 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 embodiments, hyperuricemia is determined by a serum uric acid level exceeding approximately 5.0 mg / dL. In some embodiments, hyperuricemia is determined by a serum uric acid level exceeding approximately 7.0 mg / dL.In some cases, hyperuricemia is determined by serum uric acid levels above approximately 9.0 mg / dL.

[0162] In some embodiments, one or more indicators of drug-induced nephrotoxicity include hypercalcemia, or an assessment or indicator associated with or indicating hypercalcemia. In some embodiments, the method and use herein includes assessing hypercalcemia in a subject serum sample compared to baseline levels assessed before receiving a first CNI such as cyclosporine, tacrolimus, or a derivative thereof, and selecting a subject for voclosporine administration if hypercalcemia is detected.

[0163] In some embodiments, one or more indicators of drug-induced nephrotoxicity include an increase in the fractional calcium excretion rate, or an assessment or indicator related to or indicating an increase in the fractional calcium excretion rate. In some embodiments, subjects selected for voclosporine administration show an increase of 1% or more, 5% or more, 10% or more, 15% or more, or 20% or more in the fractional calcium excretion rate assessed after receiving the first CNI, compared to the baseline fractional calcium excretion rate assessed before receiving the first CNI. In some embodiments, subjects selected for voclosporine administration show an increase of 10% or more in the fractional calcium excretion rate assessed after receiving the first CNI, compared to the baseline fractional calcium excretion rate.

[0164] In some embodiments, selected subjects exhibit a calcium fractional excretion rate of 5% or greater, 7.5% or greater, 10% or greater, 12.5% ​​or greater, or 15% or greater increase in the calcium fractional excretion rate evaluated after receiving a first CNI for immunosuppression, compared to the baseline calcium fractional excretion rate evaluated before receiving the first CNI. In some embodiments, subjects are selected for treatment if they exhibit an increase of 10% or greater in the calcium fractional excretion rate after receiving the first CNI. In some embodiments, subjects are selected for treatment if they exhibit an increase of 20% or greater in the calcium fractional excretion rate after receiving the first CNI. In some embodiments, subjects are selected for treatment if they exhibit an increase of 30% or greater in the calcium fractional excretion rate after receiving the first CNI. In some embodiments, subjects are selected for treatment if they exhibit an increase of 40% or greater in the calcium fractional excretion rate after receiving the first CNI. In some embodiments, subjects are selected for treatment if they exhibit an increase of 50% or greater in the calcium fractional excretion rate after receiving the first CNI. In some embodiments, a subject is selected for treatment if they show an increase of 60% or more in calcium fraction excretion rate after receiving a first CNI.

[0165] In some embodiments, the selected subjects exhibit a calcium fraction excretion rate of 10% or more, as assessed after receiving a first CNI for immunosuppression, compared to a baseline calcium fraction excretion rate assessed before receiving the first CNI. In some embodiments, the selected subjects exhibit a calcium fraction excretion rate of 20% or more, as assessed after receiving a first CNI for immunosuppression, compared to a baseline calcium fraction excretion rate assessed before receiving the first CNI. In some embodiments, the selected subjects exhibit a calcium fraction excretion rate of 30% or more, as assessed after receiving a first CNI for immunosuppression, compared to a baseline calcium fraction excretion rate assessed before receiving the first CNI. In some embodiments, the selected subjects exhibit a calcium fraction excretion rate of 40% or more, as assessed after receiving a first CNI for immunosuppression, compared to a baseline calcium fraction excretion rate assessed before receiving the first CNI. In some embodiments, the selected subjects exhibit a calcium fractional excretion rate of 50% or more, as assessed after receiving a first CNI for immunosuppression, compared to a baseline calcium fractional excretion rate assessed before receiving the first CNI. In some embodiments, the selected subjects exhibit a calcium fractional excretion rate of 60% or more, as assessed after receiving a first CNI for immunosuppression, compared to a baseline calcium fractional excretion rate assessed before receiving the first CNI.

[0166] In some embodiments, a subject is selected if it shows an increase in calcium fractional excretion rate. In some embodiments, the calcium fractional excretion rate is evaluated at baseline. In some embodiments, baseline is before the subject receives a first CNI such as cyclosporine, tacrolimus, or a derivative thereof. In some embodiments, the calcium fractional excretion rate is evaluated after the subject receives a first CNI such as cyclosporine, tacrolimus, or a derivative thereof. In some embodiments, a subject is selected if the calcium fractional excretion rate has increased by about 10%, 12.5%, 15%, 17.5%, or 20% or more compared to the baseline level. In some embodiments, a subject is selected if the calcium fractional excretion rate has increased by about 10% or more compared to the baseline level. In some embodiments, a subject is selected if the calcium fractional excretion rate has increased by about 12.5% ​​or more compared to the baseline level. In some embodiments, a subject is selected if the calcium fractional excretion rate has increased by about 15% or more compared to the baseline level. In some embodiments, subjects are selected when the calcium fractional excretion rate has increased by approximately 17.5% or more compared to the baseline level. In some embodiments, subjects are selected when the calcium fractional excretion rate has increased by approximately 20% or more compared to the baseline level.

[0167] In some embodiments, one or more indicators of drug-induced nephrotoxicity include an increase in the fractional calcium excretion rate, or an assessment or indicator related to or indicating an increase in the fractional calcium excretion rate. In some embodiments, subjects selected for voclosporine administration show a 2-fold, 3-fold, 4-fold, or 5-fold increase in the fractional calcium excretion rate assessed after receiving a first CNI compared to the baseline fractional calcium excretion rate assessed before receiving the first CNI. In some embodiments, subjects selected for voclosporine administration show a 2-fold or greater increase in the fractional calcium excretion rate assessed after receiving a first CNI compared to the baseline fractional calcium excretion rate. In some embodiments, subjects selected for voclosporine administration show a 3-fold or greater increase in the fractional calcium excretion rate assessed after receiving a first CNI compared to the baseline fractional calcium excretion rate. In some embodiments, subjects selected for voclosporine administration show a 4-fold or greater increase in the fractional calcium excretion rate assessed after receiving a first CNI compared to the baseline fractional calcium excretion rate. In some embodiments, subjects selected for voclosporine administration exhibit a calcium fractional excretion rate, assessed after receiving a first CNI, that is five times or more compared to the baseline calcium fractional excretion rate.

[0168] In some embodiments, selected subjects exhibit a 2-fold, 3-fold, 4-fold, or 5-fold increase in calcium fractional excretion rate, as assessed after receiving a first CNI for immunosuppression, compared to a baseline calcium fractional excretion rate assessed before receiving the first CNI. In some embodiments, subjects are selected for treatment if they exhibit a 2-fold or greater increase in calcium fractional excretion rate after receiving the first CNI. In some embodiments, subjects are selected for treatment if they exhibit a 3-fold or greater increase in calcium fractional excretion rate after receiving the first CNI. In some embodiments, subjects are selected for treatment if they exhibit a 4-fold or greater increase in calcium fractional excretion rate after receiving the first CNI. In some embodiments, subjects are selected for treatment if they exhibit a 5-fold or greater increase in calcium fractional excretion rate after receiving the first CNI. In some embodiments, subjects are selected if they exhibit an increase in calcium fractional excretion rate. In some embodiments, calcium fractional excretion rate is assessed at baseline. In some embodiments, the baseline is before the subject receives a first CNI such as cyclosporine, tacrolimus, or a derivative thereof. In some embodiments, the calcium fraction excretion rate is evaluated after the subject receives a first CNI such as cyclosporine, tacrolimus, or a derivative thereof.

[0169] In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 1% or more, 5% or more, 10% or more, 15% or more, 20% or more, 25% or more, 30% or more, 35% or more, 40% or more, 45% or more, or 50% or more in the calcium fractional excretion rate evaluated after voclosporine administration, compared to the calcium fractional excretion rate evaluated after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 10% or more in the calcium fractional excretion rate evaluated after voclosporine administration, compared to the calcium fractional excretion rate evaluated after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 25% or more in the calcium fractional excretion rate assessed after voclosporine administration compared to the calcium fractional excretion rate assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 45% or more in the calcium fractional excretion rate assessed after voclosporine administration compared to the calcium fractional excretion rate assessed after a first CNI but before voclosporine administration.

[0170] In some embodiments, subjects selected for voclosporine administration show a decrease of 2 times, 3 times, 4 times, or 5 times or more in the calcium fractional excretion rate evaluated after voclosporine administration compared to the calcium fractional excretion rate evaluated after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 2 times or more in the calcium fractional excretion rate evaluated after voclosporine administration compared to the calcium fractional excretion rate evaluated after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 3 times or more in the calcium fractional excretion rate evaluated after voclosporine administration compared to the calcium fractional excretion rate evaluated after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of more than four times in the calcium fractional excretion rate assessed after voclosporine administration compared to the calcium fractional excretion rate assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of more than five times in the calcium fractional excretion rate assessed after voclosporine administration compared to the calcium fractional excretion rate assessed after a first CNI but before voclosporine administration.

[0171] In some embodiments, the provided embodiments include assessing or monitoring the risk of drug-induced hypercalcemia by, for example, evaluating or measuring changes in one or more of the indicators described herein. In some embodiments, a subject is selected for administration of voclosporine if the subject exhibits one or more indicators associated with drug-induced hypercalcemia after administration of a first CNI.

[0172] In some embodiments, one or more indicators of drug-induced nephrotoxicity include hypercalciuria, or an assessment or indicator associated with or indicating hypercalciuria. In some embodiments, subjects selected for voclosporine administration exhibit hypercalciuria after receiving a first CNI. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 10%, 15%, 20%, 30%, 40%, or 50% or more in urinary calcium levels assessed after receiving a first CNI compared to baseline urinary calcium levels. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 10% or more in urinary calcium levels assessed after receiving a first CNI compared to baseline urinary calcium levels. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 15% or more in urinary calcium levels assessed after receiving a first CNI compared to baseline urinary calcium levels. In some embodiments, subjects selected for voclosporine administration exhibit a 20% or greater increase in urinary calcium levels assessed after receiving a first CNI compared to baseline urinary calcium levels. In some embodiments, subjects selected for voclosporine administration exhibit a 30% or greater increase in urinary calcium levels assessed after receiving a first CNI compared to baseline urinary calcium levels. In some embodiments, subjects selected for voclosporine administration exhibit a 40% or greater increase in urinary calcium levels assessed after receiving a first CNI compared to baseline urinary calcium levels. In some embodiments, subjects selected for voclosporine administration exhibit a 50% or greater increase in urinary calcium levels assessed after receiving a first CNI compared to baseline urinary calcium levels.

[0173] In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 10% or more, 15% or more, 20% or more, 30% or more, 40% or more, or 50% or more in urinary calcium levels assessed after voclosporine administration compared to urinary calcium levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 10% or more in urinary calcium levels assessed after voclosporine administration compared to urinary calcium levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 15% or more in urinary calcium levels assessed after voclosporine administration compared to urinary calcium levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 20% or more in urinary calcium levels assessed after voclosporine administration compared to urinary calcium levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 30% or more in urinary calcium levels assessed after voclosporine administration compared to urinary calcium levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 40% or more in urinary calcium levels assessed after voclosporine administration compared to urinary calcium levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a 50% or greater decrease in urinary calcium levels assessed after voclosporine administration compared to urinary calcium levels assessed after a first CNI but before voclosporine administration.

[0174] In some embodiments, subjects are selected if they have increased susceptibility to drug-induced hypercalcemia after receiving a first CNI. In some embodiments, subjects are selected if they have increased susceptibility to drug-induced hypercalcemia compared to the corresponding population. In some embodiments, the population of individuals means the entire affected population. In some embodiments, the population of individuals means the entire population of a particular sex. In some embodiments, the population of individuals means the entire population of a particular race. In some embodiments, the population of individuals means the entire population of a particular age group. In some embodiments, the population of individuals means the entire population of a particular geographical area.

[0175] In some embodiments, one or more indicators of drug-induced nephrotoxicity include an increase in the fractional magnesium excretion rate, or an assessment or indicator related to or indicating an increase in the fractional magnesium excretion rate. In some embodiments, subjects selected for voclosporine administration show an increase of 1.2 times or more, 1.3 times or more, 1.4 times or more, 1.5 times or more, 1.6 times or more, 1.7 times or more, 1.8 times or more, 1.9 times or more, or 2.0 times or more in the fractional magnesium excretion rate assessed after receiving the first CNI, compared to the baseline fractional magnesium excretion rate. In some embodiments, subjects selected for voclosporine administration show an increase of 1.2 times or more in the fractional magnesium excretion rate assessed after receiving the first CNI, compared to the baseline fractional magnesium excretion rate. In some embodiments, subjects selected for voclosporine administration show an increase of 1.3 times or more in the fractional magnesium excretion rate assessed after receiving the first CNI, compared to the baseline fractional magnesium excretion rate. In some embodiments, subjects selected for voclosporine administration exhibit a magnesium fractional excretion rate of 1.4 times or more compared to the baseline magnesium fractional excretion rate, as assessed after receiving a first CNI. In some embodiments, subjects selected for voclosporine administration exhibit a magnesium fractional excretion rate of 1.5 times or more compared to the baseline magnesium fractional excretion rate, as assessed after receiving a first CNI.

[0176] In some embodiments, selected subjects exhibit a magnesium fractional excretion rate, as assessed after receiving a first CNI for immunosuppression, that shows an increase of 1.2 times, 1.3 times, 1.4 times, or 1.5 times or more compared to the baseline magnesium fractional excretion rate assessed before receiving the first CNI. In some embodiments, subjects are selected for treatment if they show an increase of 1.2 times or more in magnesium fractional excretion rate after receiving the first CNI. In some embodiments, subjects are selected for treatment if they show an increase of 1.3 times or more in magnesium fractional excretion rate after receiving the first CNI. In some embodiments, subjects are selected for treatment if they show an increase of 1.4 times or more in magnesium fractional excretion rate after receiving the first CNI. In some embodiments, subjects are selected if they show an increase in magnesium fractional excretion rate after receiving the first CNI. In some embodiments, subjects are selected if they show an increase in magnesium fractional excretion rate. In some embodiments, magnesium fractional excretion rate is assessed at baseline. In some embodiments, the baseline is before the subject receives a first CNI such as cyclosporine, tacrolimus, or a derivative thereof. In some embodiments, the magnesium fractional excretion rate is evaluated after the subject receives a first CNI such as cyclosporine, tacrolimus, or a derivative thereof.

[0177] In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 1.2 times or more, 1.3 times or more, 1.4 times or more, 1.5 times or more, 1.6 times or more, 1.7 times or more, 1.8 times or more, 1.9 times or more, or 2.0 times or more in magnesium fractional excretion rate evaluated after voclosporine administration compared to magnesium fractional excretion rate evaluated after first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 1.2 times or more in magnesium fractional excretion rate evaluated after voclosporine administration compared to magnesium fractional excretion rate evaluated after first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 1.4 times or more in the magnesium fractional excretion rate evaluated after voclosporine administration compared to the magnesium fractional excretion rate evaluated after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 1.6 times or more in the magnesium fractional excretion rate evaluated after voclosporine administration compared to the magnesium fractional excretion rate evaluated after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 1.8 times or more in the magnesium fractional excretion rate evaluated after voclosporine administration compared to the magnesium fractional excretion rate evaluated after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a magnesium fractional excretion rate, assessed after voclosporine administration, that is 2.0 times or more lower than the magnesium fractional excretion rate assessed after a first CNI but before voclosporine administration.

[0178] In some embodiments, one or more indicators of drug-induced nephrotoxicity include elevated levels of calbindin-D28K, or assessments or indicators related to or indicating elevated levels of calbindin-D28K. In some embodiments, a subject is selected for voclosporine administration if the subject exhibits changes in calbindin-D28K levels associated with drug-induced hypercalcemia and tubular dysfunction. In some embodiments, a subject is selected for treatment if, after receiving a first CNI, the subject exhibits an increase of 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold in the level of calbindin-D28K. In some embodiments, a subject is selected for treatment if, after receiving a first CNI, the subject exhibits an increase of 2-fold or more in the level of calbindin-D28K. In some embodiments, a subject is selected for treatment if, after receiving a first CNI, the subject exhibits an increase of 3-fold or more in the level of calbindin-D28K. In some embodiments, a subject is selected for treatment if, after receiving a first CNI, the subject shows a four-fold or greater increase in the level of calbindin-D28K. In some embodiments, a subject is selected for treatment if, after receiving a first CNI, the subject shows a five-fold or greater increase in the level of calbindin-D28K. In some embodiments, a subject is selected for treatment if, after receiving a first CNI, the subject shows a six-fold or greater increase in the level of calbindin-D28K. In some embodiments, a subject is selected for treatment if, after receiving a first CNI, the subject shows a seven-fold or greater increase in the level of calbindin-D28K. In some embodiments, a subject is selected for treatment if, after receiving a first CNI, the subject shows an eight-fold or greater increase in the level of calbindin-D28K. In some embodiments, a subject is selected for treatment if, after receiving a first CNI, the subject shows a nine-fold or greater increase in the level of calbindin-D28K. In some embodiments, a subject is selected for treatment if they show a tenfold or greater increase in calbindin-D28K levels after receiving a first CNI.

[0179] In some embodiments, subjects selected for voclosporine administration exhibit a 1-fold, 1.5-fold, 2-fold, 2.5-fold, or 3-fold decrease in calbindin-D28K levels assessed after receiving a first CNI compared to baseline calcium fractional excretion rates. In some embodiments, subjects selected for voclosporine administration exhibit a 1.5-fold or greater decrease in calbindin-D28K levels assessed after receiving a first CNI compared to baseline calcium fractional excretion rates. In some embodiments, subjects selected for voclosporine administration exhibit a 2-fold or greater decrease in calbindin-D28K levels assessed after receiving a first CNI compared to baseline calcium fractional excretion rates. In some embodiments, subjects selected for voclosporine administration exhibit a 2.5-fold or greater decrease in calbindin-D28K levels assessed after receiving a first CNI compared to baseline calcium fractional excretion rates.

[0180] In some embodiments, subjects selected for voclosporine administration show a decrease of 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold or more in calbindin-D28K levels assessed after voclosporine administration compared to calbindin-D28K levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 2-fold or more in calbindin-D28K levels assessed after voclosporine administration compared to calbindin-D28K levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of more than four times in calbindin-D28K levels after voclosporine administration compared to calbindin-D28K levels after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of more than six times in calbindin-D28K levels after voclosporine administration compared to calbindin-D28K levels after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of more than eight times in calbindin-D28K levels after voclosporine administration compared to calbindin-D28K levels after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a 10-fold or greater decrease in calbindin-D28K levels assessed after voclosporine administration compared to calbindin-D28K levels assessed after a first CNI but before voclosporine administration.

[0181] In some embodiments, one or more indicators of drug-induced nephrotoxicity include elevated sodium-chloride cotransporter (NCC) levels, or assessments or indicators related to or indicating elevated sodium-chloride cotransporter (NCC) levels. In some embodiments, subjects are selected for voclosporine administration if they exhibit changes in sodium-chloride cotransporter (NCC) levels associated with drug-induced hypercalcemia and tubular dysfunction. In some embodiments, subjects are selected for treatment if they show a 2-fold, 3-fold, 4-fold, or 5-fold or greater decrease in NCC levels after receiving a first CNI. In some embodiments, subjects selected for voclosporine administration show a 1-fold, 1.5-fold, 2-fold, 2.5-fold, or 3-fold or greater decrease in sodium-chloride cotransporter (NCC) levels assessed after receiving a first CNI compared to baseline calcium fractional excretion rate. In some embodiments, subjects are selected for treatment if they show a 1.5-fold or greater increase in NCC levels after receiving a first CNI. In some embodiments, a subject is selected for treatment if, after receiving a first CNI, the subject shows a decrease of more than twofold in the level of NCC. In some embodiments, a subject is selected for treatment if, after receiving a first CNI, the subject shows a decrease of more than threefold in the level of NCC. In some embodiments, a subject is selected for treatment if, after receiving a first CNI, the subject shows a decrease of more than fourfold in the level of NCC. In some embodiments, a subject is selected for treatment if, after receiving a first CNI, the subject shows a decrease of more than fivefold in the level of NCC. In some embodiments, a subject is selected for treatment if, after receiving a first CNI, the subject shows a decrease of more than 1.5fold in the level of sodium-chloride cotransporter (NCC) as assessed after receiving a first CNI compared to the baseline level of sodium-chloride cotransporter (NCC). In some embodiments, a subject is selected for treatment of voclosporine if, after receiving a first CNI, the subject shows a decrease of more than twofold in the level of sodium-chloride cotransporter (NCC) as assessed after receiving a first CNI compared to the baseline level of sodium-chloride cotransporter (NCC).In some embodiments, subjects selected for voclosporine administration show a 3-fold or greater decrease in sodium-chloride cotransporter (NCC) levels compared to baseline levels, as assessed after receiving a first CNI. In some embodiments, subjects selected for voclosporine administration show a 4-fold or greater decrease in sodium-chloride cotransporter (NCC) levels compared to baseline levels, as assessed after receiving a first CNI. In some embodiments, subjects selected for voclosporine administration show a 5-fold or greater decrease in sodium-chloride cotransporter (NCC) levels compared to baseline levels, as assessed after receiving a first CNI.

[0182] In some embodiments, subjects selected for voclosporine administration show an increase of 1-fold, 1.5-fold, 2-fold, 2.5-fold, 3-fold, 4-fold, or 5-fold or more in sodium chloride cotransporter (NCC) levels assessed after voclosporine administration compared to sodium chloride cotransporter (NCC) levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show an increase of 2-fold or more in sodium chloride cotransporter (NCC) levels assessed after voclosporine administration compared to sodium chloride cotransporter (NCC) levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a more than 3-fold increase in sodium chloride cotransporter (NCC) levels after voclosporine administration compared to sodium chloride cotransporter (NCC) levels after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a more than 4-fold increase in sodium chloride cotransporter (NCC) levels after voclosporine administration compared to sodium chloride cotransporter (NCC) levels after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a more than 5-fold increase in sodium chloride cotransporter (NCC) levels after voclosporine administration compared to sodium chloride cotransporter (NCC) levels after a first CNI but before voclosporine administration.

[0183] In some embodiments, subjects selected for voclosporine administration exhibit a 30% or greater decrease in the expression level of one or more genes selected from the group consisting of Slc12a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8a1, and Calb1, as assessed after receiving a first CNI, compared to the baseline expression level of each of those genes assessed before receiving the first CNI. In some embodiments, subjects are selected if they exhibit a decrease in the expression level of one or more genes selected from the group consisting of Slc12a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8a1, and Calb1. In some embodiments, the expression level of one or more genes is assessed at baseline. In some embodiments, baseline is before the subject receives a first CNI such as cyclosporine, tacrolimus, or a derivative thereof. In some embodiments, the expression level of one or more genes is assessed after the subject receives a first CNI such as cyclosporine, tacrolimus, or a derivative thereof.

[0184] In some embodiments, subjects selected for voclosporine administration show an increase of 30% or more in the expression level of one or more genes selected from the group consisting of Slc12a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8a1, and Calb1, as evaluated after voclosporine administration, compared to the expression level of one or more genes selected from the group consisting of Slc12a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8a1, and Calb1, as evaluated after the first CNI but before voclosporine administration.

[0185] In some embodiments, subjects selected for voclosporin administration exhibit a decrease of 30%, 40%, 50%, 60%, or 70% or more in the expression level of the solute carrier family 12 member A3 (Slc12a3) gene, as assessed after receiving a first CNI, compared to the baseline expression level of Slc12a3 assessed before receiving the first CNI. In some embodiments, subjects selected for voclosporin administration exhibit a decrease of 30% or more in the expression level of the solute carrier family 12 member A3 (Slc12a3) gene, as assessed after receiving a first CNI, compared to the baseline expression level of Slc12a3 assessed before receiving the first CNI. In some embodiments, subjects selected for voclosporin administration exhibit a decrease of 30%, 40%, 50%, 60%, or 70% or more in the expression level of Slc12a3 compared to baseline. In some embodiments, subjects selected for voclosporin administration exhibit a decrease of 30% or more in the expression level of Slc12a3 compared to baseline.

[0186] In some embodiments, subjects selected for voclosporine administration show an increase of 30%, 40%, 50%, 60%, or 70% or more in the expression level of the solute carrier family 12 member A3 (Slc12a3) gene after voclosporine administration, compared to the expression level of the solute carrier family 12 member A3 (Slc12a3) gene after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show an increase of 30% or more in the expression level of the solute carrier family 12 member A3 (Slc12a3) gene after voclosporine administration, compared to the expression level of the solute carrier family 12 member A3 (Slc12a3) gene after a first CNI but before voclosporine administration.

[0187] In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 30%, 40%, 50%, 60%, or 70% or more in the expression level of the transient receptor potential cation channel subfamily M member 6 (Trpm6) gene, as assessed after receiving a first CNI, compared to the baseline expression level of Trpm6 assessed before receiving the first CNI. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 30% or more in the expression level of the transient receptor potential cation channel subfamily M member 6 (Trpm6) gene, as assessed after receiving a first CNI, compared to the baseline expression level of Trpm6 assessed before receiving the first CNI. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 30%, 40%, 50%, 60%, or 70% or more in the expression level of Trpm6 compared to baseline. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 30% or more in the expression level of Trpm6 compared to baseline.

[0188] In some embodiments, subjects selected for voclosporine administration show an increase of 30%, 40%, 50%, 60%, or 70% or more in the expression level of the transient receptor potential cation channel subfamily M member 6 (Trpm6) gene after voclosporine administration, compared to the expression level of the transient receptor potential cation channel subfamily M member 6 (Trpm6) gene after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show an increase of 30% or more in the expression level of the transient receptor potential cation channel subfamily M member 6 (Trpm6) gene after voclosporine administration, compared to the expression level of the transient receptor potential cation channel subfamily M member 6 (Trpm6) gene after a first CNI but before voclosporine administration.

[0189] In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 30%, 40%, 50%, 60%, or 70% or more in Cnnm2 (cyclin and CBS domain divalent metal cation transporter mediator 2) gene expression levels, as assessed after receiving a first CNI, compared to baseline Cnnm2 expression levels assessed before receiving the first CNI. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 30% or more in Cnnm2 (cyclin and CBS domain divalent metal cation transporter mediator 2) gene expression levels, as assessed after receiving a first CNI, compared to baseline Cnnm2 expression levels assessed before receiving the first CNI. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 30%, 40%, 50%, 60%, or 70% or more in Cnnm2 expression levels compared to baseline. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 30% or more in Cnnm2 expression levels compared to baseline.

[0190] In some embodiments, subjects selected for voclosporine administration show an increase of 30%, 40%, 50%, 60%, or 70% or more in the expression level of the Cnnm2 (cyclin and CBS domain divalent metal cation transporter mediator 2) gene after voclosporine administration, compared to the expression level of the Cnnm2 (cyclin and CBS domain divalent metal cation transporter mediator 2) gene after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show an increase of 30% or more in the expression level of the Cnnm2 (cyclin and CBS domain divalent metal cation transporter mediator 2) gene after voclosporine administration, compared to the expression level of the Cnnm2 (cyclin and CBS domain divalent metal cation transporter mediator 2) gene after a first CNI but before voclosporine administration.

[0191] In some embodiments, subjects selected for voclosporin administration exhibit a decrease of 30%, 40%, 50%, 60%, or 70% or more in epidermal growth factor (Egf) gene expression levels assessed after receiving a first CNI compared to baseline Egf expression levels assessed before receiving the first CNI. In some embodiments, subjects selected for voclosporin administration exhibit a decrease of 30% or more in epidermal growth factor (Egf) gene expression levels assessed after receiving a first CNI compared to baseline Egf expression levels assessed before receiving the first CNI. In some embodiments, subjects selected for voclosporin administration exhibit a decrease of 30%, 40%, 50%, 60%, or 70% or more in Egf expression levels compared to baseline. In some embodiments, subjects selected for voclosporin administration exhibit a decrease of 30% or more in Egf expression levels compared to baseline.

[0192] In some embodiments, subjects selected for voclosporin administration exhibit an increase of 30%, 40%, 50%, 60%, or 70% or more in the expression level of the epidermal growth factor (Egf) gene, as assessed after voclosporin administration, compared to the expression level of the epidermal growth factor (Egf) gene, as assessed after a first CNI but before voclosporin administration. In some embodiments, subjects selected for voclosporin administration exhibit an increase of 30% or more in the expression level of the epidermal growth factor (Egf) gene, as assessed after voclosporin administration, compared to the expression level of the epidermal growth factor (Egf) gene, as assessed after a first CNI but before voclosporin administration.

[0193] In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 30%, 40%, 50%, 60%, or 70% or more in the expression level of the calcium channel TRPV5 gene, as assessed after receiving a first CNI, compared to the baseline expression level of Trpv5 assessed before receiving the first CNI. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 30% or more in the expression level of the calcium channel TRPV5 gene, as assessed after receiving a first CNI, compared to the baseline expression level of Trpv5 assessed before receiving the first CNI. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 30%, 40%, 50%, 60%, or 70% or more in the expression level of Trpv5 compared to baseline. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 30% or more in the expression level of Trpv5 compared to baseline.

[0194] In some embodiments, subjects selected for voclosporine administration exhibit an increase of 30%, 40%, 50%, 60%, or 70% or more in the expression level of the calcium channel TRPV5 gene, as assessed after voclosporine administration, compared to the expression level of the calcium channel TRPV5 gene, as assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 30% or more in the expression level of the calcium channel TRPV5 gene, as assessed after voclosporine administration, compared to the expression level of the calcium channel TRPV5 gene, as assessed after a first CNI but before voclosporine administration.

[0195] In some embodiments, subjects selected for voclosporin administration exhibit a decrease of 30%, 40%, 50%, 60%, or 70% or more in the expression level of the solute carrier family 8 member A1 (Slc8A1) gene, as assessed after receiving a first CNI, compared to the baseline expression level of Slc8a1 assessed before receiving the first CNI. In some embodiments, subjects selected for voclosporin administration exhibit a decrease of 30% or more in the expression level of the solute carrier family 8 member A1 (Slc8A1) gene, as assessed after receiving a first CNI, compared to the baseline expression level of Slc8a1 assessed before receiving the first CNI. In some embodiments, subjects selected for voclosporin administration exhibit a decrease of 30%, 40%, 50%, 60%, or 70% or more in the expression level of Slc8a1 compared to baseline. In some embodiments, subjects selected for voclosporin administration exhibit a decrease of 30% or more in the expression level of Slc8a1 compared to baseline.

[0196] In some embodiments, subjects selected for voclosporine administration show an increase of 30%, 40%, 50%, 60%, or 70% or more in the expression level of the solute carrier family 8 member A1 (Slc8A1) gene after voclosporine administration, compared to the expression level of the solute carrier family 8 member A1 (Slc8A1) gene after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show an increase of 30% or more in the expression level of the solute carrier family 8 member A1 (Slc8A1) gene after voclosporine administration, compared to the expression level of the solute carrier family 8 member A1 (Slc8A1) gene after a first CNI but before voclosporine administration.

[0197] In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 30%, 40%, 50%, 60%, or 70% or more in the expression level of the calbindin 1 (Calb1) gene, as assessed after receiving a first CNI, compared to the baseline expression level of Calb1 assessed before receiving the first CNI. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 30% or more in the expression level of the calbindin 1 (Calb1) gene, as assessed after receiving a first CNI, compared to the baseline expression level of Calb1 assessed before receiving the first CNI. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 30%, 40%, 50%, 60%, or 70% or more in the expression level of Calb1 compared to baseline. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 30% or more in the expression level of Calb1 compared to baseline.

[0198] In some embodiments, subjects selected for voclosporine administration exhibit an increase of 30%, 40%, 50%, 60%, or 70% or more in the expression level of the calbindin 1 (Calb1) gene, as assessed after voclosporine administration, compared to the expression level of the calbindin 1 (Calb1) gene, as assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 30% or more in the expression level of the calbindin 1 (Calb1) gene, as assessed after voclosporine administration, compared to the expression level of the calbindin 1 (Calb1) gene, as assessed after a first CNI but before voclosporine administration.

[0199] In some embodiments, subjects selected for voclosporine administration have tubular dysfunction with hypophosphatemia. In some embodiments, subjects selected for voclosporine administration show a decrease of 10%, 15%, 20%, 30%, 40%, or 50% or more in serum phosphate levels as assessed after receiving a first CNI compared to baseline serum phosphate levels. In some embodiments, subjects selected for voclosporine administration show a decrease of 10% in serum phosphate levels as assessed after receiving a first CNI compared to baseline serum phosphate levels.

[0200] In some embodiments, subjects selected for voclosporine administration exhibit an increase of 10% or more, 15% or more, 20% or more, 30% or more, 40% or more, or 50% or more in serum phosphate levels assessed after voclosporine administration compared to serum phosphate levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 10% or more in serum phosphate levels assessed after voclosporine administration compared to serum phosphate levels assessed after a first CNI but before voclosporine administration.

[0201] In some embodiments, subjects selected for voclosporine administration exhibit a lower natriuretic response. In some embodiments, subjects selected for voclosporine administration show a decrease of 10%, 15%, 20%, 30%, 40%, or 50% or more in the natriuretic response assessed after receiving a first CNI compared to the baseline natriuretic response. In some embodiments, subjects selected for voclosporine administration exhibit a lower natriuretic response. In some embodiments, subjects selected for voclosporine administration show a decrease of 10% or more in the natriuretic response assessed after receiving a first CNI compared to the baseline natriuretic response.

[0202] In some embodiments, subjects selected for voclosporine administration exhibit an increase of 10% or more, 15% or more, 20% or more, 30% or more, 40% or more, or 50% or more in the natriuretic response assessed after voclosporine administration compared to the natriuretic response assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 10% or more in the natriuretic response assessed after voclosporine administration compared to the natriuretic response assessed after a first CNI but before voclosporine administration.

[0203] In some embodiments, subjects selected for voclosporine administration exhibit a lower saline diuretic response. In some embodiments, subjects selected for voclosporine administration show a decrease of 10% or more, 15% or more, 20% or more, 30% or more, 40% or more, or 50% or more in saline diuretic response assessed after receiving a first CNI, compared to baseline saline diuretic response. In some embodiments, subjects selected for voclosporine administration exhibit a lower saline diuretic response. In some embodiments, subjects selected for voclosporine administration show a decrease of 10% or more in saline diuretic response assessed after receiving a first CNI, compared to baseline saline diuretic response.

[0204] In some embodiments, subjects selected for voclosporine administration show an increase of 10% or more, 15% or more, 20% or more, 30% or more, 40% or more, or 50% or more in the saline diuretic response assessed after voclosporine administration compared to the saline diuretic response assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show an increase of 10% or more in the saline diuretic response assessed after voclosporine administration compared to the saline diuretic response assessed after a first CNI but before voclosporine administration.

[0205] In some embodiments, subjects selected for voclosporine administration have tubular dysfunction with hypertension. In some embodiments, subjects selected for voclosporine administration show an increase of 10%, 15%, 20%, 30%, 40%, or 50% or more in blood pressure as assessed after receiving a first CNI compared to baseline blood pressure. In some embodiments, subjects selected for voclosporine administration show a 10% increase in blood pressure as assessed after receiving a first CNI compared to baseline blood pressure.

[0206] In some embodiments, subjects selected for voclosporine administration exhibit an increase of ≥10%, ≥15%, ≥20%, ≥30%, ≥40%, or ≥50% in plasma endothelin-1 levels as assessed after receiving a first CNI, compared to baseline plasma endothelin-1 levels.

[0207] In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 10%, 15%, 20%, 30%, 40%, or 50% or more in plasma endothelin-1 levels assessed after voclosporine administration, compared to plasma endothelin-1 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 10% or more in plasma endothelin-1 levels assessed after voclosporine administration, compared to plasma endothelin-1 levels assessed after a first CNI but before voclosporine administration.

[0208] In some embodiments, subjects selected for voclosporine administration exhibit a cyclooxygenase-2 expression level, as assessed after receiving a first CNI, that is 10% or greater, 15% or greater, 20% or greater, 30% or greater, 40% or greater, or 50% or greater compared to the baseline cyclooxygenase-2 expression level. In some embodiments, subjects selected for voclosporine administration exhibit a cyclooxygenase-2 expression level, as assessed after receiving a first CNI, that is 10% or greater compared to the baseline cyclooxygenase-2 expression level.

[0209] In some embodiments, subjects selected for voclosporine administration exhibit an increase of 10% or more, 15% or more, 20% or more, 30% or more, 40% or more, or 50% or more in cyclooxygenase-2 expression levels assessed after voclosporine administration compared to cyclooxygenase-2 expression levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 10% or more in cyclooxygenase-2 expression levels assessed after voclosporine administration compared to cyclooxygenase-2 expression levels assessed after a first CNI but before voclosporine administration.

[0210] In some embodiments, subjects selected for voclosporine administration have tubular dysfunction with metabolic acidosis. In some embodiments, subjects selected for voclosporine administration show an increase of 10%, 15%, 20%, 30%, 40%, or 50% or more in metabolic acidosis as assessed after receiving a first CNI, compared to a baseline level of metabolic acidosis. In some embodiments, subjects selected for voclosporine administration show a 10% increase in metabolic acidosis as assessed after receiving a first CNI, compared to a baseline level of metabolic acidosis.

[0211] In some embodiments, subjects selected for voclosporine administration exhibit a reduction of 10% or more, 15% or more, 20% or more, 30% or more, 40% or more, or 50% or more in metabolic acidosis levels assessed after voclosporine administration compared to metabolic acidosis levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a reduction of 10% or more in metabolic acidosis levels assessed after voclosporine administration compared to metabolic acidosis levels assessed after a first CNI but before voclosporine administration.

[0212] D. Renal biopsy Renal biopsies of CNI-induced chronic nephrotoxicity reveal primary endothelial damage (e.g., indicated by obstructive arteriolar disease), vasoconstriction, glomerular ischemic collapse or scarring, tubular vacuolation, and / or whole-segmental and focal-segmental glomerulosclerosis. Furthermore, interstitial fibrosis and tubular atrophy (IFTA) occur in the lesion. See, for example, Buelow 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 consistent decrease in glomerular filtration rate (GFR).

[0213] In some embodiments, one or more indicators of drug-induced nephrotoxicity are assessed based on one or more renal biopsies. Renal biopsies reveal obstructive arteriolar disease, indicating primary endothelial damage, in relation to chronic conventional drug-induced nephrotoxicity. Nephrotoxic renal biopsies may also show vasoconstriction, glomerular ischemic collapse or scarring, tubular vacuolation, whole-segmental and focal segmental glomerulosclerosis, as well as lesional interstitial fibrosis and tubular atrophy (IFTA). In some embodiments, interstitial fibrosis and tubular atrophy are observed together. In some embodiments, subjects with remission of proteinuria may exhibit histological activity. In some embodiments, subjects without remission of proteinuria may exhibit histological activity. In some embodiments, renal biopsies are collected at various time points. In some embodiments, subjects are evaluated for repeated renal biopsies, including those collected before administration of the first CNI and after the initiation of administration of the first CNI.

[0214] The biopsy may be evaluated using light microscopy, immunofluorescence microscopy, or electron microscopy. The collected renal biopsy may be evaluated by hematoxylin-eosin staining (H&E), periodate Schiff (PAS), silver staining, trichrome staining, and collagen III immunohistochemistry. Renal biopsies may also be stained with immunofluorescence for C3, C4, C5, C1q, IgG, IgM, and IgA, etc., though this is not limited to these. Renal biopsies may be semi-quantitatively graded using the following categories: Grade 0: <5%, Grade 1: 5-25%, Grade 2: 25-50%, Grade 3: >50%. These categories represent the percentage of non-scarring cortical areas involving mononuclear cell infiltration and are analogous to the Banff interstitial inflammation score for renal allograft rejection. Trichrome staining is used to help identify fibrosis.

[0215] In some embodiments, renal biopsies collected at baseline and after administration of the first CNI may be examined to identify the presence of interstitial fibrosis and tubular atrophy. Interstitial fibrosis is identified as an accumulation of collagen and related molecules in the interstitium. Tubular atrophy is identified as small tubules containing cells with clear cytoplasm, or dilated, thin tubules.

[0216] In some embodiments, one or more indicators of drug-induced nephrotoxicity include interstitial fibrosis and tubular atrophy, or an assessment or indicator related to or indicating interstitial fibrosis and tubular atrophy. In some embodiments, the methods disclosed herein include assessing interstitial fibrosis and tubular atrophy in a subject by renal biopsy compared to baseline levels, and selecting a subject for voclosporine administration if interstitial fibrosis and tubular atrophy are observed in a cortical area exceeding a predetermined percentage compared to baseline levels.

[0217] In some embodiments, the predetermined percentage is one of 0%, 1%, 2%, 5%, 10%, 15%, 20%, 25%, or 50%, or any percentage in between. In some embodiments, the predetermined percentage is 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 one of 5% or less, 5% to 25%, 25% to 50% or less, or greater than 50%. In some embodiments, the predetermined percentage is about 5% or less. In some embodiments, the predetermined percentage is about 5%. In some embodiments, the predetermined percentage is greater than about 5%. In some embodiments, interstitial fibrosis and tubular atrophy are assessed by the involvement of mononuclear cell infiltration in non-scarring cortical areas, which is analogous to the Banff interstitial inflammation score for kidney allograft rejection. In some embodiments, the percentage of non-scarring cortical areas involving mononuclear cell infiltration is assessed by hematoxylin-eosin staining (H&E), periodate Schiff (PAS), silver staining, and trichrome staining, as well as collagen III immunohistochemistry, and is semi-quantitatively graded using the following categories: Grade 0: ≤5%, Grade 1: 5–25%, Grade 2: ≤25–50%, Grade 3: ≥50%. In some embodiments, subjects are selected for voclosporine administration if, based on renal biopsy, they exhibit interstitial fibrosis and tubular atrophy observed in more than 5% of the cortical area after receiving a first CNI.

[0218] In some embodiments, renal biopsies collected at baseline and after administration of the first CNI may be evaluated for renal injury, including glomerular injury. In some embodiments, renal biopsies collected at baseline and after administration of the first CNI may be evaluated for glomerular injury, such as whole-segmental glomerulosclerosis. In some embodiments, whole-segmental glomerulosclerosis is identified by the presence of arteriolar hyalinization, arteriolar disease, secondary glomerular ischemia, and / or atrophic tubuloglomeruli.

[0219] In some embodiments, one or more indicators of drug-induced nephrotoxicity include glomerular injury, or an assessment or indicator related to or indicating glomerular injury. In some embodiments, the method and use herein includes assessing the presence of glomerular injury in a subject by renal biopsy compared to baseline levels, and selecting a subject for voclosporine administration if glomerular injury is present compared to baseline levels.

[0220] In some embodiments, renal biopsies collected at baseline and after administration of the first CNI may be evaluated for arteriole medial hyalinization. The presence of nodular hyaline deposits in the media of the afferent arteriole is identified by the replacement of necrotic smooth muscle cells at the outer margin of the afferent arteriole wall with localized or circular clumps of protein (hyaline). Further investigation includes evaluation of vascular lumen narrowing, which is negatively associated with favorable renal outcomes.

[0221] In some embodiments, one or more indicators of drug-induced nephrotoxicity include arterioleoluminescence, or an assessment or indicator related to or indicating arterioleoluminescence. In some embodiments, the method and use herein includes assessing the presence of arterioleoluminescence in a subject by renal biopsy compared to baseline levels, and selecting a subject for voclosporine administration if arterioleoluminescence is present compared to baseline levels. In some embodiments, arterioleoluminescence is identified by the replacement of necrotic smooth muscle cells at the outer margin of the afferent arteriole wall with localized round, lumpy protein (hyaline) deposits, and narrowing of the vascular lumen. In some embodiments, arterioleoluminescence is identified by the replacement of necrotic smooth muscle cells at the outer margin of the afferent arteriole wall with localized round, lumpy protein (hyaline) deposits, or narrowing of the vascular lumen. In some embodiments, a subject is selected for voclosporine administration if, based on renal biopsy, the subject exhibits arterioleomedia hyalinization after undergoing a first CNI. In some embodiments, arterioleomedia hyalinization is identified by the replacement of necrotic smooth muscle cells in the outer margin of the afferent arteriole wall with localized, round, lumpy protein (hyaluronic acid) deposits and / or narrowing of the vascular lumen.

[0222] In some embodiments, one or more indicators of drug-induced nephrotoxicity include atrophic glomeruli, or assessments or indicators related to or indicating atrophic glomeruli. In some embodiments, renal biopsies collected at baseline and after administration of the first CNI may be assessed for atrophic glomeruli. The presence of atrophic glomeruli is characterized by the presence of glomeruli detached from the proximal tubule. Atrophic glomeruli can also be identified by the presence of peri-glomerular fibrosis (capsular fibrosis) or the presence of significantly contracted glomeruli within dilated glomerular cysts.

[0223] In some embodiments, one or more indicators of drug-induced nephrotoxicity include glomerulosclerosis, or an assessment or indicator related to or indicating glomerulosclerosis. In some embodiments, renal biopsies collected at baseline and after administration of the first CNI may be assessed for focal segmental glomerulosclerosis. A lesion of focal segmental glomerulosclerosis is identified by the presence of sclerosis in a portion of at least one glomerulus and is identified as approximately 12.5 percent of the total glomerular volume. In some embodiments, renal injury includes whole-segmental and segmental glomerulosclerosis, tubular atrophy, interstitial fibrosis, and arteriosclerosis. In some embodiments, renal injury includes whole-segmental and segmental glomerulosclerosis, tubular atrophy, interstitial fibrosis, or arteriosclerosis. In some examples, renal injury is present when the total renal chronicity score is greater than 1. To assess kidney injury, whole-segmental 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. These scores are then added together (total renal chronicity score) to grade the overall severity of the chronic lesion as very mild (total score 0 to 1), mild (total score 2 to 4), moderate (total score 5 to 7), and severe (total score 8 or higher). In some embodiments, kidney injury is determined to be present when the total renal chronicity score is greater than any one of 0, 1, 2, 3, 4, 5, 6, 7, or 8. In some embodiments, kidney injury is determined to be present when the total renal chronicity score is about 1, about 2 to about 4, about 5 to about 7, or about 8 to about 10. In some embodiments, kidney injury includes mild glomerular injury (total score 2 to 4). In some embodiments, renal injury includes moderate glomerular injury (total score 5-7). In some embodiments, renal injury includes severe glomerular injury (total score 8 or higher).

[0224] In some embodiments, a subject is selected for voclosporine administration if, based on renal biopsy, the subject exhibits renal injury, including arteriolar medial hyalinization, after undergoing a first CNI. In some embodiments, renal injury is identified by the presence of whole-segmental and segmental glomerulosclerosis, tubular atrophy, interstitial fibrosis, and / or arteriosclerosis, as well as a total renal chronicity score > 1.

[0225] In some embodiments, the 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 may be evaluated to determine the NIH-AI, NIH-CI, or TIAI.

[0226] In some embodiments, the National Institutes of Health Activity Index (NIH-AI) is used to assess disease activity, including a histological measure of inflammation. In some embodiments, one or more indicators of drug-induced nephrotoxicity include an increase in NIH-AI, or an assessment or indicator associated with or indicating an increase in NIH-AI. In some embodiments, the NIH-AI score is determined based on a component score, which may include endocapillary pleochromacy, neutrophils and nuclear disintegration, hyaline deposition and wire loops, fibrinoid necrosis, cellular or fibrous crescents, and interstitial inflammation. In some embodiments, the NIH-AI is calculated based on the sum of the component scores. In some embodiments, the NIH-AI includes scoring the percentage of glomeruli exhibiting each of the following features in a biopsy on a scale of 0 to 3 (score 0 = none, 1 = less than 25% of glomeruli, 2 = 25-50% of glomeruli, 3 = greater than 50% of glomeruli).

[0227] In some embodiments, the NIH-AI component score includes a score for intracapsular pleoplasia on a scale of 0–3. In some embodiments, the NIH-AI component score includes a score for neutrophils and nuclear decay on a scale of 0–3. In some embodiments, the NIH-AI component score includes a score for hyaline deposition and wire loops on a scale of 0–3. In some embodiments, the NIH-AI component score includes a score for fibrinoid necrosis on a scale of (0–3) × 2. In some embodiments, the NIH-AI component score includes a score for cellular or fibrous crescent formation on a scale of (0–3) × 2. Fibrinoid necrosis and crescent formation are weighted twice as much due to their significant negative impact on prognosis. In some embodiments, the NIH-AI component score includes a score for interstitial inflammation on a scale of 0–3.

[0228] In some embodiments, the NIH-AI score includes one or more component scores, and the total score out of 24 is used. In some embodiments, the total NIH-AI score includes all component scores, and the total score out of 24 is used. The score range is 0 to 24, where 0 is considered inactive. A high NIH-AI value (>6) is considered a high level of renal injury.

[0229] In some embodiments, subjects are selected for voclosporine administration if they show an increase in the National Institutes of Health Activity Index (NIH-AI) on a renal biopsy assessed after the first CNI, compared to their baseline NIH-AI. In some embodiments, subjects are selected for voclosporine administration if they show an increase of 10%, 20%, 30%, 40%, or 50% or more in their NIH-AI assessed after the first CNI, compared to their baseline NIH-AI. In some embodiments, subjects are selected for voclosporine administration if they show an increase of 10% or more in their NIH-AI assessed after the first CNI, compared to their baseline NIH-AI. In some embodiments, subjects are selected for voclosporine administration if they show an increase of 20% or more in their NIH-AI assessed after the first CNI, compared to their baseline NIH-AI. In some embodiments, a subject is selected for voclosporine administration if their NIH-AI, assessed after receiving a first CNI, shows an increase of 30% or more compared to their baseline NIH-AI. In some embodiments, a subject is selected for voclosporine administration if their NIH-AI, assessed after receiving a first CNI, shows an increase of 40% or more compared to their baseline NIH-AI. In some embodiments, a subject is selected for voclosporine administration if their NIH-AI, assessed after receiving a first CNI, shows an increase of 50% or more compared to their baseline NIH-AI.

[0230] In some embodiments, subjects selected for voclosporine administration are those who, after receiving voclosporine, show a reduction of 10%, 20%, 30%, 40%, or 50% or more in NIH-AI assessed after receiving voclosporine, compared to NIH-AI assessed after receiving a first CNI but before receiving voclosporine.

[0231] In some embodiments, subjects are selected for voclosporine administration if they exhibit an NIH-AI score of 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 or higher after receiving a first CNI. In some embodiments, subjects are selected for voclosporine administration if they exhibit an NIH-AI score of 3 or higher after receiving a first CNI. In some embodiments, subjects are selected for voclosporine administration if they exhibit an NIH-AI score of 4 or higher after receiving a first CNI. In some embodiments, subjects are selected for voclosporine administration if they exhibit an NIH-AI score of 5 or higher after receiving a first CNI. In some embodiments, subjects are selected for voclosporine administration if they exhibit an NIH-AI score of 6 or higher after receiving a first CNI. In some embodiments, subjects are selected for voclosporine administration if they exhibit an NIH-AI score of 7 or higher after receiving a first CNI. In some embodiments, a subject is selected for voclosporine administration if they have an NIH-AI score of 8 or higher after receiving a first CNI. In some embodiments, a subject is selected for voclosporine administration if they have an NIH-AI score of 9 or higher after receiving a first CNI. In some embodiments, a subject is selected for voclosporine administration if they have an NIH-AI score of 10 or higher after receiving a first CNI. In some embodiments, a subject is selected for voclosporine administration if they have an NIH-AI score of 11 or higher after receiving a first CNI. In some embodiments, a subject is selected for voclosporine administration if they have an NIH-AI score of 12 or higher after receiving a first CNI.

[0232] In some embodiments, the National Institutes of Health (NIH) Chronicity Index (NIH-CI) is used to assess the degree of chronicity, including irreversible kidney injury and scarring associated with end-stage renal disease. In some embodiments, one or more indicators of drug-induced nephrotoxicity include an increase in the NIH-CI, or an assessment or indicator that is associated with or indicates an increase in the NIH-CI. In some embodiments, the NIH-CI score is determined based on component scores that may include whole-segmental and segmental glomerulosclerosis, fibrous crescents, tubular atrophy, or interstitial fibrosis. In some embodiments, the NIH-CI is calculated based on the sum of the component scores.

[0233] In some embodiments, the NIH-CI component score includes scores for whole-segmental and segmental glomerulosclerosis on a scale of 0 to 3. In some embodiments, the NIH-CI component score includes scores for fibrous crescents on a scale of 0 to 3. In some embodiments, the NIH-CI component score includes scores for tubular atrophy on a scale of 0 to 3. In some embodiments, the NIH-CI component score includes scores for interstitial fibrosis on a scale of 0 to 3.

[0234] In some embodiments, the NIH-CI includes one or more component scores, and a total score out of 12 is used. In some embodiments, the total NIH-CI score includes all component scores, and a total score out of 12 is used. In some embodiments, the component scores are summed up (total renal chronicity score), and the overall severity of chronic lesions is graded as very mild (total score 0-1), mild (total score 2-4), moderate (total score 5-7), and severe (total score ≥8). The NIH-CI index includes the total percentage of total glomerulosclerosis, fibrous crescents, tubular atrophy, and interstitial fibrosis. The NIH-CI score range is 0-12, with 0 representing no chronicity. High NIH-CI values ​​(>3) are correlated with progression to renal failure.

[0235] In some embodiments, if the subject shows an increase of 10%, 20%, 30%, 40%, or 50% or more in the NIH-CI evaluated after receiving the first CNI compared to the baseline NIH-CI, the subject is selected for administration of tacrolimus. In some embodiments, if the subject shows an increase in the National Institutes of Health Chronicity Index (NIH-CI) in a renal biopsy evaluated after receiving the first CNI compared to the baseline NIH-CI, the subject is selected for administration of tacrolimus. In some embodiments, if the subject shows an increase of 10% or more in the NIH-CI evaluated after receiving the first CNI compared to the baseline NIH-CI, the subject is selected for administration of tacrolimus. In some embodiments, if the subject shows an increase of 20% or more in the NIH-CI evaluated after receiving the first CNI compared to the baseline NIH-CI, the subject is selected for administration of tacrolimus. In some embodiments, if the subject shows an increase of 30% or more in the NIH-CI evaluated after receiving the first CNI compared to the baseline NIH-CI, the subject is selected for administration of tacrolimus. In some embodiments, if the subject shows an increase of 40% or more in the NIH-CI evaluated after receiving the first CNI compared to the baseline NIH-CI, the subject is selected for administration of tacrolimus. In some embodiments, if the subject shows an increase of 50% or more in the NIH-CI evaluated after receiving the first CNI compared to the baseline NIH-CI, the subject is selected for administration of tacrolimus.

[0236] In some embodiments, a subject selected for administration of tacrolimus shows a decrease of 10%, 20%, 30%, 40%, or 50% or more in the NIH-CI evaluated after receiving tacrolimus compared to the NIH-CI evaluated after receiving the first CNI but before receiving tacrolimus.

[0237] In some embodiments, if a subject exhibits an NIH-CI score of 3, 4, 5, 6 or more after receiving a first CNI, the subject is selected for administration of voriconazole. In some embodiments, if a subject exhibits an NIH-CI score of 3 or more after receiving a first CNI, the subject is selected for administration of voriconazole. In some embodiments, if a subject exhibits an NIH-CI score of 4 or more after receiving a first CNI, the subject is selected for administration of voriconazole. In some embodiments, if a subject exhibits an NIH-CI score of 5 or more after receiving a first CNI, the subject is selected for administration of voriconazole. In some embodiments, if a subject exhibits an NIH-CI score of 6 or more after receiving a first CNI, the subject is selected for administration of voriconazole.

[0238] 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]

[0239] In some embodiments, the method and use herein include evaluating one or more of the following by renal biopsy: 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 compared to baseline levels, and selecting the subject for voclosporine administration if the NIH-AI, NIH-CI, and / or TIAI are outside a predetermined range compared to baseline levels. In some embodiments, the predetermined range of NIH-AI is one of approximately 0-1, 0-2, 0-3, 0-4, 0-5, 0-6, 0-7, 0-8, 0-9, 0-10, 0-11, 0-12, 0-13, 0-14, 0-15, 0-16, 0-17, 0-18, 0-19, or 0-20. In some embodiments, a predetermined range for NIH-AI is 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 for NIH-AI is approximately 0 to 6. In some embodiments, a predetermined range for NIH-CI is one of approximately 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, a predetermined range for NIH-CI is one of <1, <2, <3, <4, <5, <6, <7, <8, <9, or <10. In some embodiments, the predetermined range for NIH-CI is approximately 0 to 3. In some embodiments, a predetermined range for TIAI is one of approximately 0-1, 0-2, 0-3, 0-4, 0-5, 0-6, 0-7, 0-8, 0-9, 0-10, 0-11, 0-12, 0-13, 0-14, or 0-15. In some embodiments, a predetermined range for NIH-AI is one of <1, <2, <3, <4, <5, <6, <7, <8, <9, <10, <11, <12, <13, <14, or <15. In some embodiments, a predetermined range for TIAI is approximately 0-5. In some embodiments, a predetermined range for NIH-AI is approximately 0-6, or a predetermined range for NIH-CI is approximately 0-3, and / or a predetermined range for TIAI is approximately 0-5.In some embodiments, the predetermined range of NIH-AI is 0 to 6, the predetermined range of NIH-CI is 0 to 3, or the predetermined range of TIAI is 0 to 5.

[0240] Regarding TIAI, the nuclear concentration, nuclear activation, necrosis, flattening of tubular cells, macrophages in the tubular lumen, epithelial cells in the tubular lumen, and interstitial inflammation are evaluated. The TIAI score range is 0 to 21, with 0 representing no interstitial activity. In some embodiments, one or more indicators of drug-induced nephrotoxicity include an increase in TIAI, or an evaluation or indicator associated with or indicating an increase in TIAI. In some embodiments, a subject is selected for voclosporine administration if their TIAI, as assessed after receiving a first CNI, shows an increase of 10% or more compared to their baseline TIAI. In some embodiments, a subject is selected for voclosporine administration if their TIAI score is 3 or higher after receiving a first CNI.

[0241] In some embodiments, renal biopsies collected at baseline and after administration of the first CNI may be evaluated for juxtaglomerular apparatus (JGA) hyperplasia. The renal biopsies are stained with Masson and immunoperoxidase stains and subjected to immunohistochemical analysis. The samples are further analyzed by electron microscopy. JGA hyperplasia is evaluated by hypertrophy of the components of the juxtaglomerular apparatus, including vascular components (part of the afferent and efferent arterioles), mesangial cell components (altered extraglomerular and intraglomerular smooth muscle cells), and tubular components (macula densa), as well as the presence of intracellular renin granules.

[0242] In some embodiments, one or more indicators of drug-induced nephrotoxicity include the presence of juxtaglomerular apparatus (JGA) hyperplasia, or an assessment or indicator associated with or indicating JGA hyperplasia. In some embodiments, the methods disclosed herein further include assessing the presence of JGA hyperplasia in a subject by renal biopsy compared to baseline levels, and selecting a subject for voclosporine administration if JGA hyperplasia is present compared to baseline levels. In some examples, JGA hyperplasia includes hypertrophy of components of the juxtaglomerular apparatus, including one or more of the vascular components, mesangial cellular components, and tubular components (macula densa), and the presence of intracellular renin granules.

[0243] In some embodiments, renal biopsies collected at baseline and after the administration of the first CNI may be evaluated for tubular microcalcification. In some embodiments, histological slides of undecalcified formalin (4%) fixed paraffin-embedded biopsies are analyzed with hematoxylin-eosin (H&E) and periodate Schiff (PAS) staining, as well as von Kossa and alizarin staining to visualize calcium phosphate deposition. Electron microscopy is used to further identify calcium deposition within the renal tubules. The density of microcalcification is evaluated as the number of calcified lesions per square millimeter of biopsy, and is calculated by dividing the total number of calcified lesions observed in the biopsy by the total area of ​​the biopsy measured on the slide (number of lesions per square millimeter).

[0244] In some embodiments, one or more indicators of drug-induced nephrotoxicity include tubular microcalcification, or an assessment or indicator related to or indicating tubular microcalcification. In some embodiments, the methods disclosed herein further include assessing the presence of tubular microcalcification in a subject by renal biopsy compared to baseline levels, and selecting a subject for voclosporine administration if tubular microcalcification is present compared to baseline levels.

[0245] In some embodiments, renal biopsies collected at baseline and after administration of the first CNI can be evaluated for P-glycoprotein (P-gp) expression to determine whether the renal biopsy reveals a loss of P-gp expression outside a predetermined range. P-glycoprotein expression is analyzed by staining the renal biopsy with an anti-P-glycoprotein antibody. P-glycoprotein expression in glomerular and tubular epithelial cells is semi-quantitatively scored according to its intensity and distribution. The classification includes: normal = 0 points, loss of P-gp expression in less than 10% of tubules located in the cortical region; mild loss = 1 point, loss of P-gp expression in 10% to 24% of tubules located in the cortical region; moderate loss = 2 points, loss of P-gp expression in 25% to 50% of tubules located in the cortical region; severe loss = 3 points, loss of P-gp expression in more than 50% of tubules located in the cortical region. Decreased P-glycoprotein expression is associated with renal lesions. In some embodiments, the classification of P-glycoprotein expression includes mild loss. In some embodiments, the classification of P-glycoprotein expression includes moderate loss. In some embodiments, the classification of P-glycoprotein expression includes severe loss.

[0246] In some embodiments, one or more indicators of drug-induced nephrotoxicity include P-gp expression, or an assessment or indicator related to or indicating P-gp expression. In some embodiments, the methods disclosed herein further include assessing P-gp expression in a subject by renal biopsy compared to baseline levels, and selecting the subject for voclosporine administration if the loss of P-gp expression compared to baseline levels exceeds a predetermined value. In some examples, the predetermined value for loss of P-gp expression is a 10% loss of P-gp expression in the cortical tubules. P-glycoprotein expression in glomerular and tubular epithelial cells can be semi-quantitatively scored according to its intensity and distribution. The classification may include: Normal = 0 points, loss of P-gp expression in less than 10% of tubules located in the cortical region; Mild loss = 1 point, loss of P-gp expression in 10% to 24% of tubules located in the cortical region; Moderate loss = 2 points, loss of P-gp expression in 25% to 50% of tubules located in the cortical region; Severe loss = 3 points, loss of P-gp expression in more than 50% of tubules located in the cortical region. In some embodiments, a predetermined value for loss of P-gp expression is a loss of approximately 5% to approximately 50% of P-gp expression in the cortical region tubules. In some embodiments, a predetermined value for loss of P-gp expression is one of the following: loss of approximately 5%, 8%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50% of P-gp expression in the cortical region tubules. In some embodiments, a predetermined value for P-gp expression loss is one of the following: approximately 1% to approximately 5%, approximately 5% to approximately 10%, approximately 10% to approximately 25%, approximately 25% to approximately 50%, or 50% or more of P-gp expression in the cortical tubules. In some examples, a predetermined value for P-gp expression loss is a 10% loss of P-gp expression in the cortical tubules. In some embodiments, a subject is selected for voclosporine administration if, based on renal biopsy, the subject shows a loss of 10% or more of P-glycoprotein (P-gp) expression, as assessed after receiving a first CNI, compared to baseline P-gp expression.

[0247] In some embodiments, renal biopsies collected at baseline and after administration of the first CNI can be evaluated to determine the drug-induced nephrotoxicity score or the Banff chronicity score (BChS) and to determine whether the renal biopsy reveals a drug-induced nephrotoxicity score of BChS outside a predetermined range.

[0248] In some embodiments, one or more indicators of drug-induced nephrotoxicity include drug-induced nephrotoxicity and / or Banff score, or an assessment or indicator related to or indicating drug-induced nephrotoxicity and / or Banff score. In some embodiments, the method disclosed herein further includes assessing the drug-induced nephrotoxicity and / or Banff score of a subject by renal biopsy compared to a baseline level, and selecting the subject for voclosporine administration if the CNI nephrotoxicity and / or Banff score is outside a predetermined range compared to a baseline level. In some embodiments, the predetermined range of the CNI nephrotoxicity score is one of about 0-1, 0-2, 0-3, 0-4, 0-5, 0-6, 0-7, 0-8, 0-9, or 0-10. In some embodiments, the predetermined range of the CNI nephrotoxicity score is one of about <1, <2, <3, <4, <5, <6, <7, <8, <9, or <10. In some embodiments, a predetermined range for the Banff score is one of approximately 0-1, 0-2, 0-3, 0-4, 0-5, 0-6, 0-7, 0-8, 0-9, or 0-10. In some embodiments, a predetermined range for the Banff score is one of approximately <1, <2, <3, <4, <5, <6, <7, <8, <9, or <10. In some embodiments, a predetermined range for the CNI nephrotoxicity score is 0-3, or a predetermined range for the Banff score is 0-3. In some embodiments, a subject is selected for voclosporine administration if, based on renal biopsy, the subject exhibits a drug-induced nephrotoxicity score of 0-3 after undergoing a first CNI. In some embodiments, a subject is selected for voclosporine administration if, based on renal biopsy, the subject exhibits a Banff score of 0-3 after undergoing a first CNI.

[0249] In grading the severity of chronic changes, biopsies can be scored semi-quantitatively. In some embodiments, the CNI nephrotoxicity score is assessed based on six parameters graded on a scale of 0 to 3, resulting in a possible total score of 18. The six parameters include (1) homogeneous tubular vacuolation (tv), (2) hyaline of the arteriole margin or media (ah), (3) striped interstitial fibrosis, (4) glomerular ischemic collapse, (5) juxtaglomerular apparatus hyperplasia, and (6) tubular dystrophic calcification. To determine the Banff Chronicity Score (BChS), a renal biopsy is analyzed for transplant glomerulopathy (cg), tubular atrophy (ct), interstitial fibrosis (ci), and chronic vascular changes (cv), and graded on a scale of 0 to 3. The severity of renal lesions is classified as mild, moderate, and severe. In some embodiments, the classification of renal lesions includes mild severity. In some embodiments, the classification of renal lesions includes moderate severity. In some embodiments, the classification of renal lesions includes severe severity.

[0250] E. Drug-drug interactions In some embodiments, subjects are selected if they exhibit drug interactions with other drugs or immunosuppressants commonly administered with a CNI after administration of a first CNI. In some embodiments, because many different immunosuppressants are commonly administered together, adverse effects of conventional CNIs on other immunosuppressants may lead to reduced therapeutic efficacy. In some embodiments, if a subject receiving a conventional CNI as the first CNI in combination with another drug exhibits drug interactions such as a decrease in the blood levels of the other drug, the subject is selected for administration of voclosporine, which has been observed to exhibit only very low levels of drug interactions and adverse effects on the other drug.

[0251] In some embodiments, one or more indicators of drug interaction include an assessment or indicator related to or indicating a decrease in blood levels of mycophenolate (MPA) after prior administration of a first CNI in combination with mycophenolate mofetil (MMF) for immunosuppression. In some embodiments, the method and use herein involves selecting a subject that exhibits a decrease in blood levels of MPA after prior administration of a first CNI in combination with MMF for immunosuppression, the first CNI comprising cyclosporine, tacrolimus, or a derivative thereof. In some embodiments, voclosporine is administered to the selected subject.

[0252] The active portion of MMF is MPA. MPA is metabolized in the liver to the inactive metabolite MPA glucuronide (MPAG). MPAG is excreted into the bile by multidrug resistance-associated protein 2 (MRP2). MPAG is deconjugated back to MPA via enterohepatic circulation, particularly in the small intestine, and reabsorbed into the circulation, contributing to MPA exposure (see Van Gelder et al., Nephrol Dial Transplant, 2022 37:917-922).

[0253] The blood level of MPA is the peak serum concentration (C). max ) or area under the concentration curve (AUC) from 0 to 12 hours 0-12) is determined to be a selected subject. In some embodiments, the selected subject shows a decrease of 1.0, 1.5, 2.0, 2.5, or 3.0 times or more in the blood level of MPA assessed after receiving the first CNI compared to the baseline blood level of MPA assessed before receiving the first CNI. In some embodiments, the selected subject shows a decrease of 1.0 times or more in the blood level of MPA assessed after receiving the first CNI compared to the baseline blood level of MPA. In some embodiments, the selected subject shows a decrease of 1.5 times or more in the blood level of MPA assessed after receiving the first CNI compared to the baseline blood level of MPA. In some embodiments, the selected subject shows a decrease of 2.0 times or more in the blood level of MPA assessed after receiving the first CNI compared to the baseline blood level of MPA.

[0254] In some embodiments, subjects selected for voclosporine administration show an increase of 1.0, 1.5, 2.0, 2.5, or 3.0 times or more in blood MPA levels assessed after voclosporine administration compared to blood MPA levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show an increase of 1.0 times or more in blood MPA levels assessed after voclosporine administration compared to blood MPA levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show an increase of 1.5 times or more in blood MPA levels assessed after voclosporine administration compared to blood MPA levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a 2.0-fold or greater increase in blood MPA levels assessed after voclosporine administration compared to blood MPA levels assessed after a first CNI but before voclosporine administration.

[0255] F. Serum Lipid Profile In some embodiments, the method and use herein include evaluating the level of one or more lipids in a subject compared to a baseline level, and selecting a subject for voclosporine administration if the level of one or more lipids is outside a predetermined range. In some embodiments, one or more indicators of dyslipidemia include evaluations or indicators that relate to or indicate an increase in serum lipids or inflammatory lipids, or an increase in any of the specific lipids described herein.

[0256] In some embodiments, one or more lipids include ceramide (CER). In some embodiments, one or more lipids include dihydroceramide (DCER). In some embodiments, one or more lipids include monoacylglycerol (MAG). In some embodiments, one or more lipids include saturated diacylglycerol. In some embodiments, one or more lipids include lysophosphatidylcholine. In some embodiments, one or more lipids include phosphatidylinositol (PI). In some embodiments, one or more lipids include sphingomyelin (SM). In some embodiments, one or more lipids include triacylglycerol (TAG).

[0257] In some embodiments, the subject selected for administration of voriconazole shows an increase of 15% or more, 20% or more, 25% or more, or 30% or more compared to the baseline level of TAG at the level of TAG evaluated after receiving the first CNI. In some embodiments, the subject selected for administration of voriconazole shows an increase of 15% or more compared to the baseline level of TAG at the level of TAG evaluated after receiving the first CNI. In some embodiments, the subject selected for administration of voriconazole shows an increase of 20% or more compared to the baseline level of TAG at the level of TAG evaluated after receiving the first CNI. In some embodiments, the subject selected for administration of voriconazole shows an increase of 25% or more compared to the baseline level of TAG at the level of TAG evaluated after receiving the first CNI. In some embodiments, the subject selected for administration of voriconazole shows an increase of 30% or more compared to the baseline level of TAG at the level of TAG evaluated after receiving the first CNI.

[0258] In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 15%, 20%, 25%, or 30% or more in TAG levels assessed after voclosporine administration compared to TAG levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 15% or more in TAG levels assessed after voclosporine administration compared to TAG levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 20% or more in TAG levels assessed after voclosporine administration compared to TAG levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 25% or more in TAG levels assessed after voclosporine administration compared to TAG levels assessed before voclosporine administration but after a first CNI. In some embodiments, subjects selected for voclosporine administration show a decrease of 30% or more in TAG levels assessed after voclosporine administration compared to TAG levels assessed before voclosporine administration but after a first CNI.

[0259] In some embodiments, subjects selected for voclosporine administration exhibit an increase of 15%, 20%, 25%, or 30% or more in ceramide (CER) levels assessed after receiving a first CNI compared to baseline CER levels. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 15% or more in ceramide (CER) levels assessed after receiving a first CNI compared to baseline CER levels. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 20% or more in ceramide (CER) levels assessed after receiving a first CNI compared to baseline CER levels. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 25% or more in ceramide (CER) levels assessed after receiving a first CNI compared to baseline CER levels. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 30% or more in ceramide (CER) levels assessed after receiving a first CNI compared to baseline CER levels.

[0260] In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 15%, 20%, 25%, or 30% or more in the CER level assessed after voclosporine administration compared to the CER level assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 15% or more in the CER level assessed after voclosporine administration compared to the CER level assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 20% or more in the CER level assessed after voclosporine administration compared to the CER level assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 25% or more in the CER level assessed after voclosporine administration compared to the CER level assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 30% or more in the CER level assessed after voclosporine administration compared to the CER level assessed after a first CNI but before voclosporine administration.

[0261] In some embodiments, one or more lipids are selected from one or more of total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides.

[0262] In some embodiments, subjects selected for voclosporine administration exhibit an increase of 15%, 20%, 25%, or 30% or more in low-density lipoprotein (LDL) cholesterol levels assessed after receiving a first CNI compared to baseline LDL levels.

[0263] In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 15%, 20%, 25%, or 30% or more in LDL levels assessed after voclosporine administration compared to LDL levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 15% or more in LDL levels assessed after voclosporine administration compared to LDL levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 20% or more in LDL levels assessed after voclosporine administration compared to LDL levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 25% or more in LDL levels assessed after voclosporine administration compared to LDL levels assessed before voclosporine administration but after a first CNI. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 30% or more in LDL levels assessed after voclosporine administration compared to LDL levels assessed before voclosporine administration but after a first CNI.

[0264] In some embodiments, the lipid is total cholesterol, and the specified range is less than 170 mg / dL, or 100-200 mg / dL, or 125-200 mg / dL. In some embodiments, the lipid is total cholesterol, and the specified range is 100-200 mg / dL. In some embodiments, the lipid is triglycerides, and the specified range is less than 150 mg / dL, or 50-150 mg / dL. In some embodiments, the lipid is triglycerides, and the specified range is 50-150 mg / dL. In some embodiments, the lipid is LDL, and the specified range is less than 100, 110, 120, or 130 mg / dL, or 10-130, 30-130, or 50-130 mg / dL. In some embodiments, the lipid is LDL, and the specified range is 50-130 mg / dL. In some embodiments, the lipid is HDL, and the predetermined range is 40, 45, or 50 mg / dL or higher, or 35 to 60 mg / dL. In some embodiments, the lipid is LDL, and the predetermined range is 35 to 60 mg / dL.

[0265] G. Glucose dysregulation In some embodiments, the methods provided herein include selecting subjects who exhibit one or more indicators of new-onset diabetes after having previously received a first CNI for immunosuppression. In some embodiments, one or more indicators of new-onset diabetes are evaluated based on any known method for evaluating or diagnosing diabetes, including evaluations related to insulin signaling, glucose metabolism, or regulation.

[0266] In some embodiments, voclosporine is administered to the selected subjects. In some embodiments, the newly developed diabetes is new-onset diabetes mellitus (NODAT) after transplantation.

[0267] In some embodiments, one or more indicators of new-onset diabetes include total insulin secretion or islet cell death, or an assessment or indicator related to or indicating total insulin secretion or islet cell death. In some embodiments, subjects selected for voclosporin administration exhibit inhibited total insulin secretion. In some embodiments, subjects selected for voclosporin administration exhibit islet cell death.

[0268] In some embodiments, one or more indicators of new-onset diabetes include an assessment of direct and indirect modulogenic factors of exocytosis, or an assessment or indicator related to or indicating an assessment of direct and indirect modulogenic factors of exocytosis. In some embodiments, the method and use herein includes assessing direct and indirect modulogenic factors of exocytosis in comparison to baseline levels and selecting subjects for voclosporine administration if inhibition of the modulogenic factors is observed.

[0269] In some embodiments, the regulatory factor is SYT16. In some embodiments, the regulatory factor is TBC1D30. In some embodiments, the regulatory factor is PCK1. In some embodiments, the regulatory factor is SMOC1. In some embodiments, the regulatory factor is SYT5. In some embodiments, the regulatory factor is PDK4. In some embodiments, the regulatory factor is CREM.

[0270] In some embodiments, subjects are selected if they have increased susceptibility to new-onset diabetes after receiving a first CNI. In some embodiments, subjects are selected if they have increased susceptibility to new-onset diabetes compared to a corresponding population. In some embodiments, a population of individuals means the entire affected population. In some embodiments, a population of individuals means the entire population of a particular sex. In some embodiments, a population of individuals means the entire population of a particular race. In some embodiments, a population of individuals means the entire population of a particular age group. In some embodiments, a population of individuals means the entire population of a particular geographical area. In some aspects, the embodiments provided include assessing or monitoring the risk of new-onset diabetes by, for example, evaluating or measuring changes in one or more of the indicators described herein, or one or more of the indicators described herein.

[0271] H. Biomarkers In some embodiments, biomarkers may be used to identify subjects who may be experiencing kidney injury, inflammation, and fibrosis. In some embodiments, one or more indicators of drug-induced nephrotoxicity include an increase in biomarkers associated with kidney injury, inflammation, and fibrosis, or an assessment or indicator that is associated with or indicates an increase in biomarkers associated with kidney injury, inflammation, and fibrosis. In some embodiments, the method and use herein includes assessing the level of one or more biomarkers that promote urinary tract kidney injury and fibrosis in a subject, such as cyclosporine, tacrolimus, or derivatives thereof, compared to baseline levels, and selecting a subject for voclosporine administration if the level of one or more biomarkers that promote urinary tract kidney injury and fibrosis is outside a predetermined range.

[0272] In some embodiments, one or more biomarkers include kidney injury molecule 1 (KIM-1). In some embodiments, one or more biomarkers include neutrophil gelatinase-associated lipocalin (NGAL). In some embodiments, one or more biomarkers include monocyte chemotactic protein 1 (MCP-1). In some embodiments, one or more biomarkers include transforming growth factor beta (TGF-β1). In some embodiments, one or more biomarkers include leukocyte differentiation antigen 163 (CD163). In some embodiments, one or more biomarkers include leukocyte differentiation antigen 206 (CD206). In some embodiments, one or more biomarkers include interleukin-16 (IL-16).

[0273] In some embodiments, subjects selected for voclosporine administration show an increase of 15%, 20%, 25%, or 30% or more in the level of kidney injury molecule 1 (KIM-1) assessed after receiving a first CNI compared to the baseline level of KIM-1. In some embodiments, subjects selected for voclosporine administration show an increase of 15% or more in the level of kidney injury molecule 1 (KIM-1) assessed after receiving a first CNI compared to the baseline level of KIM-1. In some embodiments, subjects selected for voclosporine administration show an increase of 20% or more in the level of KIM-1 assessed after receiving a first CNI compared to the baseline level of KIM-1. In some embodiments, subjects selected for voclosporine administration show an increase of 25% or more in the level of KIM-1 assessed after receiving a first CNI compared to the baseline level of KIM-1. In some embodiments, subjects selected for voclosporine administration show an increase of 30% or more in the level of KIM-1 assessed after receiving a first CNI compared to the baseline level of KIM-1.

[0274] In some embodiments, subjects selected for voclosporine administration show a decrease of 15%, 20%, 25%, or 30% or more in KIM-1 levels assessed after voclosporine administration compared to KIM-1 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 15% or more in KIM-1 levels assessed after voclosporine administration compared to KIM-1 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 20% or more in KIM-1 levels assessed after voclosporine administration compared to KIM-1 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 25% or more in KIM-1 levels assessed after voclosporine administration compared to KIM-1 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 30% or more in KIM-1 levels assessed after voclosporine administration compared to KIM-1 levels assessed after a first CNI but before voclosporine administration.

[0275] In some embodiments, subjects selected for voclosporine administration exhibit an increase of 15%, 20%, 25%, or 30% or more in neutrophil gelatinase-associated lipocalin (NGAL) levels assessed after receiving a first CNI compared to baseline NGAL levels. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 15% or more in neutrophil gelatinase-associated lipocalin (NGAL) levels assessed after receiving a first CNI compared to baseline NGAL levels. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 20% or more in NGAL levels assessed after receiving a first CNI compared to baseline NGAL levels. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 25% or more in NGAL levels assessed after receiving a first CNI compared to baseline NGAL levels. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 30% or more in NGAL levels assessed after receiving a first CNI compared to baseline NGAL levels.

[0276] In some embodiments, subjects selected for voclosporine administration show a decrease of 15%, 20%, 25%, or 30% or more in NGAL levels assessed after voclosporine administration compared to NGAL levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 15% or more in NGAL levels assessed after voclosporine administration compared to NGAL levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 20% or more in NGAL levels assessed after voclosporine administration compared to NGAL levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 25% or more in NGAL levels assessed after voclosporine administration compared to NGAL levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 30% or more in NGAL levels assessed after voclosporine administration compared to NGAL levels assessed after a first CNI but before voclosporine administration.

[0277] In some embodiments, subjects selected for voclosporine administration show an increase of 15%, 20%, 25%, or 30% or more in monocyte chemotactic protein 1 (MCP-1) levels assessed after receiving a first CNI compared to baseline levels of MCP-1. In some embodiments, subjects selected for voclosporine administration show an increase of 15% or more in monocyte chemotactic protein 1 (MCP-1) levels assessed after receiving a first CNI compared to baseline levels of MCP-1. In some embodiments, subjects selected for voclosporine administration show an increase of 20% or more in MCP-1 levels assessed after receiving a first CNI compared to baseline levels of MCP-1. In some embodiments, subjects selected for voclosporine administration show an increase of 25% or more in MCP-1 levels assessed after receiving a first CNI compared to baseline levels of MCP-1. In some embodiments, subjects selected for voclosporine administration exhibit an elevation of 30% or more in MCP-1 levels assessed after receiving a first CNI compared to baseline levels of MCP-1.

[0278] In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 15%, 20%, 25%, or 30% or more in MCP-1 levels assessed after voclosporine administration compared to MCP-1 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 15% or more in MCP-1 levels assessed after voclosporine administration compared to MCP-1 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 20% or more in MCP-1 levels assessed after voclosporine administration compared to MCP-1 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 25% or more in MCP-1 levels assessed after voclosporine administration compared to MCP-1 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 30% or more in MCP-1 levels assessed after voclosporine administration compared to MCP-1 levels assessed after a first CNI but before voclosporine administration.

[0279] In some embodiments, subjects selected for voclosporine administration show an increase of 15%, 20%, 25%, or 30% or more in transforming growth factor beta (TGF-β1) levels assessed after receiving a first CNI compared to baseline levels of TGF-β1. In some embodiments, subjects selected for voclosporine administration show an increase of 15% or more in transforming growth factor beta (TGF-β1) levels assessed after receiving a first CNI compared to baseline levels of TGF-β1. In some embodiments, subjects selected for voclosporine administration show an increase of 20% or more in TGF-β1 levels assessed after receiving a first CNI compared to baseline levels of TGF-β1. In some embodiments, subjects selected for voclosporine administration show an increase of 25% or more in TGF-β1 levels assessed after receiving a first CNI compared to baseline levels of TGF-β1. In some embodiments, subjects selected for voclosporine administration exhibit a TGF-β1 level of 30% or greater compared to baseline levels, as assessed after receiving a first CNI.

[0280] In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 15%, 20%, 25%, or 30% or more in TGF-B1 levels assessed after voclosporine administration compared to TGF-B1 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 15% or more in TGF-B1 levels assessed after voclosporine administration compared to TGF-B1 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 20% or more in TGF-B1 levels assessed after voclosporine administration compared to TGF-B1 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 25% or more in TGF-B1 levels assessed after voclosporine administration compared to TGF-B1 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 30% or more in TGF-B1 levels assessed after voclosporine administration compared to TGF-B1 levels assessed after a first CNI but before voclosporine administration.

[0281] In some embodiments, subjects selected for voclosporine administration exhibit an increase of 15%, 20%, 25%, or 30% or more in leukocyte differentiation antigen 163 (CD163) levels assessed after receiving a first CNI compared to baseline CD163 levels. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 15% or more in leukocyte differentiation antigen 163 (CD163) levels assessed after receiving a first CNI compared to baseline CD163 levels. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 20% or more in CD163 levels assessed after receiving a first CNI compared to baseline CD163 levels. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 25% or more in CD163 levels assessed after receiving a first CNI compared to baseline CD163 levels. In some embodiments, subjects selected for voclosporine administration exhibit an elevation of 30% or more in CD163 levels assessed after receiving a first CNI compared to baseline CD163 levels.

[0282] In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 15%, 20%, 25%, or 30% or more in CD163 levels assessed after voclosporine administration compared to CD163 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 15% or more in CD163 levels assessed after voclosporine administration compared to CD163 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 20% or more in CD163 levels assessed after voclosporine administration compared to CD163 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 25% or more in CD163 levels assessed after voclosporine administration compared to CD163 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 30% or more in CD163 levels assessed after voclosporine administration compared to CD163 levels assessed after a first CNI but before voclosporine administration.

[0283] In some embodiments, subjects selected for voclosporine administration exhibit an increase of 15%, 20%, 25%, or 30% or more in leukocyte differentiation antigen 206 (CD206) levels assessed after receiving a first CNI compared to the baseline level of CD206. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 15% or more in leukocyte differentiation antigen 206 (CD206) levels assessed after receiving a first CNI compared to the baseline level of CD206. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 20% or more in CD206 levels assessed after receiving a first CNI compared to the baseline level of CD206. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 25% or more in CD206 levels assessed after receiving a first CNI compared to the baseline level of CD206. In some embodiments, subjects selected for voclosporine administration exhibit an elevation of 30% or more in CD206 levels, as assessed after receiving a first CNI, compared to baseline CD206 levels.

[0284] In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 15%, 20%, 25%, or 30% or more in CD206 levels assessed after voclosporine administration compared to CD206 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 15% or more in CD206 levels assessed after voclosporine administration compared to CD206 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration exhibit a decrease of 20% or more in CD206 levels assessed after voclosporine administration compared to CD206 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 25% or more in CD206 levels assessed after voclosporine administration compared to CD206 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 30% or more in CD206 levels assessed after voclosporine administration compared to CD206 levels assessed after a first CNI but before voclosporine administration.

[0285] In some embodiments, subjects selected for voclosporine administration exhibit an increase of 15%, 20%, 25%, or 30% or more in interleukin-16 (IL-16) levels assessed after receiving a first CNI compared to baseline levels of IL-16. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 15% or more in interleukin-16 (IL-16) levels assessed after receiving a first CNI compared to baseline levels of IL-16. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 20% or more in IL-16 levels assessed after receiving a first CNI compared to baseline levels of IL-16. In some embodiments, subjects selected for voclosporine administration exhibit an increase of 25% or more in IL-16 levels assessed after receiving a first CNI compared to baseline levels of IL-16. In some embodiments, subjects selected for voclosporine administration exhibit an elevation of 30% or more in IL-16 levels compared to baseline levels, as assessed after receiving a first CNI.

[0286] In some embodiments, subjects selected for voclosporine administration show a decrease of 15%, 20%, 25%, or 30% or more in IL-16 levels assessed after voclosporine administration compared to IL-16 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 15% or more in IL-16 levels assessed after voclosporine administration compared to IL-16 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 20% or more in IL-16 levels assessed after voclosporine administration compared to IL-16 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 25% or more in IL-16 levels assessed after voclosporine administration compared to IL-16 levels assessed after a first CNI but before voclosporine administration. In some embodiments, subjects selected for voclosporine administration show a decrease of 30% or more in IL-16 levels assessed after voclosporine administration compared to IL-16 levels assessed after a first CNI but before voclosporine administration.

[0287] In some embodiments, subjects are selected if they exhibit one or more of the following: (a) altered expression and / or activity of P-glycoprotein, (b) altered expression and / or activity of CYP3A4 / 5, (c) advanced renal age, (d) salt depletion, (e) use of nonsteroidal anti-inflammatory drugs, and / or (f) genetic polymorphisms of TGF-β and / or ACE genes. In some embodiments, subjects exhibit upregulation of local renal P-glycoprotein. In some embodiments, subjects exhibit upregulation of local renal P-glycoprotein by approximately 20%, 40%, 50%, 75%, 100%, 20%, 50%, 75%, 100%, 500%, 1000% or more compared to the corresponding population described above. In some embodiments, subjects exhibit one or more single nucleotide polymorphisms in the ABCB1 gene. In some embodiments, subjects exhibit the TT genotype at position 3435 of the ABCB1 gene. In some embodiments, subjects exhibit the TT genotype at position 3435 of the ABCB1 gene in the transplanted kidney. In some embodiments, subjects do not exhibit the TT genotype at position 2677 of the ABCB1 gene. In some embodiments, subjects do not exhibit the TT genotype at position 2677 of the ABCB1 gene in the transplanted kidney. In some embodiments, subjects are selected if they have been exposed to or administered nonsteroidal anti-inflammatory drugs. In some embodiments, subjects exhibit a high renal age, such as one of the following high renal ages, approximately 1, 2, 3, 4, 5, 8, 10, 12, 15, 18, 20, 25, 30, 35, or 40 higher than the corresponding population described above. In some embodiments, subjects exhibit salt depletion, such as depletion of up to 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, or more compared to the corresponding population described above. In some embodiments, subjects exhibit salt depletion as a result of dietary sodium restriction. In some embodiments, salt depletion in the subject results in increased drug reabsorption into the renal tubules, such as drug reabsorption of any one of the following drugs: approximately 20%, 40%, 50%, 75%, 100%, 2x, 5x, 10x, 20x, 50x, 75x, 100x, 500x, 1000x, or more, compared to the corresponding population described above.In some embodiments, the subject exhibits one or more polymorphisms in the CYP3A4 and / or CYP3A5 genes. In some embodiments, the subject is a CYP3A5*1 carrier. In some embodiments, CYP3A5 in the liver and interstitial tissue of the subject is expressed from CYP3A5*1. In some embodiments, the subject is a CYP3A5*1 carrier, and the production of tacrolimus metabolites in the liver of the subject is one of the following: 20%, 40%, 50%, 75%, 100%, 2x, 5x, 10x, 20x, 50x, 75x, 100x, 500x, 1000x or more compared to the production in the corresponding population described above. In some embodiments, the subject exhibits genetic polymorphisms in TGF-β and / or angiotensin-converting enzyme (ACE). In some embodiments, subjects are selected if they have increased ACE activity, for example, one of the following increased levels: approximately 20%, 40%, 50%, 75%, 100%, 2x, 5x, 10x, 20x, 50x, 75x, 100x, 500x, 1000x, or more. In some embodiments, subjects are selected if they have elevated serum ACE levels, for example, one of the following elevated levels: approximately 20%, 40%, 50%, 75%, 100%, 2x, 5x, 10x, 20x, 50x, 75x, 100x, 500x, 1000x, or more. In some embodiments, subjects exhibit a TGF-β polymorphism at codon 10. In some embodiments, subjects exhibit increased local TGF-β production in allografts. In some embodiments, subjects are selected if they have an upregulation of TGF-β in tubular epithelial cells, such as an upregulation of TGF-β by approximately 20%, 40%, 50%, 75%, 100%, 2x, 5x, 10x, 20x, 50x, 75x, 100x, 500x, 1000x or more.

[0288] I. Liver function In some embodiments, subjects are selected if they exhibit hepatic impairment after receiving a first CNI. In some embodiments, subjects exhibit mild hepatic impairment (Child-Pugh A) or moderate hepatic impairment (Child-Pugh B). In some embodiments, voclosporin C max and / or AUC is increased in subjects with hepatic impairment compared to corresponding subjects without such impairment. In some embodiments, vocrossporin C max In subjects with mild or moderate hepatic impairment, the voclosporine AUC increases by approximately 1.1 times, 1.2 times, 1.3 times, 1.4 times, 1.5 times, 1.6 times, 1.7 times, 1.8 times, 1.9 times, 2.0 times, 3.0 times, 5.0 times, 10.0 times, or more, compared to a corresponding subject without such impairment. In some embodiments, the voclosporine AUC increases by approximately 1.1 times, 1.2 times, 1.4 times, 1.6 times, 1.8 times, 2.0 times, 2.2 times, 2.4 times, 2.6 times, 2.8 times, 3.0 times, 4.0 times, 5.0 times, 10.0 times, or more, compared to a corresponding subject without such impairment.

[0289] III. Administration of voclosporine In some embodiments, subjects are administered voclosporine after having previously received a first CNI (e.g., cyclosporine, tacrolimus, or a derivative thereof) for immunosuppression. In some embodiments, voclosporine is administered to selected subjects according to the criteria described herein. In some embodiments, administration of the first CNI is discontinued and voclosporine is administered to the subject. In some embodiments, according to the provided embodiments, subjects requiring CNI therapy switch their CNI from a conventional CNI (e.g., cyclosporine, tacrolimus, or a derivative thereof) to voclosporine.

[0290] In some embodiments, voclosporine is administered in doses and timings that conform to known, recommended, approved, or typical treatment regimens for voclosporine. In some embodiments, exemplary doses, timings, and treatment regimens for voclosporine are described herein. In some embodiments, the doses, timings, and treatment regimens for voclosporine may be adjusted based on modifications to recommended or approved treatment regimens.

[0291] A. Composition In some embodiments, compositions comprising voclosporine are used in the methods and uses provided. In some embodiments, subjects treated according to the provided embodiments are subjects requiring immunosuppression, such as intermittent, long-term, or even lifelong immunosuppression using CNIs such as voclosporine or pharmaceutically acceptable salts thereof. In some embodiments, compositions comprising voclosporine, a therapeutically effective dose thereof, and / or voclosporine or pharmaceutically acceptable salts thereof are used in the provided compositions, methods and uses. Uses include the use of voclosporine or compositions comprising the same in such methods, e.g., therapeutic or prophylactic methods, and treatments, e.g., therapeutic regimens, as well as the use of voclosporine, pharmaceutically acceptable salts thereof, or compositions comprising the same in the preparation of agents for performing such therapeutic or prophylactic methods and treatments.

[0292] Voclosporine (VCS), described in U.S. Patent No. 9,765,119 (which is incorporated herein by reference in whole), is a superior CNI due to its low toxicity and dose-modulation capabilities to maximize patient tolerance and efficacy. In some embodiments, voclosporine is administered to patients requiring CNI therapy in combination with additional therapeutic agents, including basal immunosuppressive therapy. In some embodiments, voclosporine exhibits a linear pharmacokinetic profile resulting in a consistent dose-concentration relationship. In some embodiments, voclosporine offers the advantage of eliminating the need for therapeutic drug monitoring, which is common with the use of CNIs. In some embodiments, voclosporine provides a predictable pharmacokinetic profile, resulting in the elimination of therapeutic drug monitoring required with other CNIs.

[0293] Compared to cyclosporine A (CsA), voclosporine has a functional group modification at one amino acid residue of the molecule, which enhances its binding to calcineurin and results in better metabolic stability. Voclosporine has been tested in psoriasis and kidney transplantation and was recently approved by the FDA for the treatment of active lupus nephritis (LN) in combination with basal immunosuppressive therapy. Observations have shown that VCS is more potent at a therapeutic level and less toxic than other immunosuppressants in its class.

[0294] VCS has been shown to inhibit norovirus replication in a CypA-dependent manner and more effectively than CsA. This modification alters the binding of voclosporine to calcineurin, and has been shown to increase binding affinity by up to 5-fold compared to CsA both in vitro and in vivo (Kuglstatter et al., Acta Cryst. 2011; D67: 119-23). ​​This modification also altered the metabolic profile of voclosporine by shifting metabolism away from amino acid-1, the major metabolic site of CsA. This change in metabolic profile leads to faster excretion of metabolites and less exposure to metabolites compared to CsA. The combination of higher potency of voclosporine and less exposure to metabolites compared to CsA leads to a better PK / PD relationship, reduced dosage, and a potentially improved safety profile compared to CsA.

[0295] Voclosporine is a cyclosporine analog modified with a 1,3-diene substituent at a 1-amino acid residue. Voclosporine may exist as an isomer mixture of Z and E isomers, and in some embodiments, it may be a mixture containing at least about 90% (e.g., about 90% to about 95%) of E isomers and about 10% or less (e.g., about 10% to about 5%) of Z isomers. In some embodiments, a voclosporine composition comprises an isomer mixture of voclosporine or a pharmaceutically acceptable salt thereof, which comprises about 90% to about 95% of E isomers and about 10% to about 5% of Z isomers. In some embodiments, a voclosporine composition comprises an isomer mixture of voclosporine or a pharmaceutically acceptable salt thereof, which comprises about 90% to about 95% of E isomers and about 10% to about 5% of Z isomers. Boxrosporine has the structure shown below and is disclosed in U.S. Patent No. 7,332,472, which is incorporated herein by reference as a whole. [ka]

[0296] Boclosporine is 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-((1R,2R,E)-1-hydroxy-2-methylhepta-4,6-dien-1-yl)-6,9,18,24-tetraisobutyl-3,21-diisopropyl-1,4,7,10,12,15,19,25,28-nonamethyl-1,4,7,10 ,13,16,19,22,25,28,31-Undecazacyclotriacontane-2,5,8,11,14,17,20,23,26,29,32-Undecaone, or (3S,6S,9S,12R,15S,18S,21S,24S,30S,33S)-30-ethyl-33-[(1R,2R,4E)-1-hydroxy-2-methylhepta-4,6-dienyl]- It is sometimes called 1,4,7,10,12,15,19,25,28-nonamethyl-6,9,18,24-tetrakis(2-methylpropyl)-3,21-di(propan-2-yl)-1,4,7,10,13,16,19,22,25,28,31-undecazacyclotriacontane-2,5,8,11,14,17,20,23,26,29,32-undecone. Vocrossporine is a registered trademark of LUPKYNIS, ISA. TXAlso known as 247, ISA247, LX211, or Luveniq. In some embodiments, references to voclosporine and administration of voclosporine may also include pharmaceutically acceptable salts of voclosporine and administration of pharmaceutically acceptable salts of voclosporine. In some embodiments, the term “pharmaceutically acceptable salt” means any salt of the compound (e.g., voclosporine) that is known to be non-toxic and is commonly used in the pharmaceutical literature. In some embodiments, pharmaceutically acceptable salts of voclosporine retain the biological efficacy of voclosporine and are not biologically or otherwise undesirable.

[0297] Bocrosporin is C 63 H 111 N 11 O 12 It has the empirical formula and a molecular weight of 1214.6 g / mol. At ambient temperature, voclosporine is readily soluble in acetone, acetonitrile, ethanol, and methanol, and substantially insoluble in heptane (USP). Voclosporine is substantially insoluble in water (less than 0.1 g / L at 20°C) and melts with decomposition above 144°C.

[0298] In some embodiments of the methods and uses provided herein, the method or treatment comprises administering voclosporine or a pharmaceutically acceptable salt thereof together with a therapeutically effective amount of MMF and / or a therapeutically effective amount of corticosteroid. In some embodiments, the method treatment comprises administering voclosporine or a pharmaceutically acceptable salt thereof without a therapeutically effective amount of MMF and / or a therapeutically effective amount of corticosteroid.

[0299] In some embodiments, the method and use described herein involves administering a composition comprising voclosporine, for example, a pharmaceutical composition or a therapeutic composition.

[0300] In some embodiments, a composition containing voclosporine includes an isomer mixture of the E and Z isomers of voclosporine. A mixture of the E and Z isomers of voclosporine is described in U.S. Patent No. 6,998,385. A mixture in which the E isomer is dominant is described in U.S. Patent No. 7,332,472, which describes exemplary indications (including glomerulonephritis) that can be treated with an isomerized voclosporine mixture. Various formulations of voclosporine mixtures are also described in U.S. Patents No. 7,060,672, No. 7,429,562, and No. 7,829,533. In some embodiments, the isomer mixture contains at least about 99% by weight, about 98% by weight, about 97% by weight, about 96% by weight, about 95% by weight, about 94% by weight, about 93% by weight, about 92% by weight, about 91% by weight, about 90% by weight, about 80% by weight, about 70% by weight, about 60% by weight, about 50% by weight, about 40% by weight, about 30% by weight, about 20% by weight, or about 10% by weight of the vocrossporine E isomer. In some embodiments, the isomer mixture contains at least 90% by weight of the vocrossporine E isomer. In some embodiments, the isomer mixture contains at least 95% by weight of the vocrossporine E isomer.

[0301] In some embodiments, the pharmaceutical composition (e.g., including voclosporine) is a pharmaceutical formulation or comprises a pharmaceutical formulation. In some embodiments, the pharmaceutical composition comprises one or more pharmaceutically acceptable excipients, buffers, carriers and / or media. In some embodiments, the pharmaceutical composition comprises a pharmaceutical carrier and excipients suitable for the intended type of administration.

[0302] In some embodiments, the generally accepted pharmaceutically acceptable carrier or medium, such as those present in a pharmaceutically acceptable buffer, may be any known in the art. (Remington's Pharmaceutical Sciences, by EW Martin, Mack Publishing Co., Easton, Pa., 19) thEdition (1995) describes compositions and formulations suitable for the pharmaceutically acceptable delivery of one or more therapeutic compounds. Pharmacopoeias are generally prepared in accordance with generally accepted pharmacopoeias for use in animals and humans, taking into consideration approval from regulatory bodies or other organizations.

[0303] Pharmaceutical compositions may include carriers administered with the compound, such as diluents, adjuvants, excipients, or media. Examples of suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences" by EW Martin. Such compositions generally contain a therapeutically effective amount of the compound in a purified form, along with an appropriate amount of carrier, providing a form for appropriate administration to the patient. Such pharmaceutical carriers may be sterile solutions, such as water, and oils, including those of petroleum, animal, plant, or synthetic origin. When the pharmaceutical composition is administered intravenously, water is the usual carrier. Saline solutions and aqueous solutions of dextrose and glycerol can also be used as liquid carriers, particularly for injectable formulations. Compositions may also optionally contain small amounts of wetting or emulsifying agents or pH buffers. Typically, compositions containing the compound are formulated into pharmaceutical compositions using techniques and procedures well known in the art (see, for example, Ansel Introduction to Pharmaceutical Dosage Forms, Fourth Edition, 1985, 126). Generally, the mode of formulation depends on the route of administration. Exemplary formulations of voclosporine mixtures are also described in U.S. Patents No. 7,060,672, No. 7,429,562, and No. 7,829,533.

[0304] B. Dosage and timing of voclosporine administration In some embodiments, voclosporine is administered in a predetermined daily dose of 39.5 mg BID, 31.6 mg BID, 23.7 mg BID, 15.8 mg BID, or 7.9 mg BID. In some embodiments, the predetermined daily dose is one of approximately 7.9–23.7, 23.7–31.6, 31.6–39.5, or 39.5–79 mg of voclosporine. In some embodiments, the predetermined daily dose is approximately 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, 40, 60, 80, 100 mg of voclosporine, or any value in between.

[0305] In some embodiments, the first time point is one of approximately 0.1, 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 12, 16, 24, 36, or 48 hours before the start of voclosporine treatment. In some embodiments, the first time point is immediately before the start of voclosporine treatment. In some embodiments, the second time point is one of approximately 1, 2, 3, 4, 5, 10, 14, 15, 20, 25, 28, 30, 40, 50 days or more after the start of voclosporine treatment, or any period in between. In some embodiments, the second time point is approximately 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 weeks or more after the initiation of vocrossporine treatment, or any period in between.

[0306] In some embodiments, a prescribed daily dose of voclosporine that is effective is any one of approximately 5, 7.9, 10, 12, 15, 15.8, 20, 23.7, 25, 28, 30, 31.6, 35, 39.5, 40, 45, or 50 mg BIDs, or any amount in between. In some embodiments, a prescribed daily dose of voclosporine is 39.5 mg BID, 31.6 mg BID, 23.7 mg BID, 15.8 mg BID, or 7.9 mg BID.

[0307] In some embodiments, subjects have severe renal impairment at baseline, and the prescribed daily effective dose of voclosporine is one of approximately 2, 5, 7.9, 10, 12, 15, 15.8, 20, 23.7, 25, 28, 30, 31.6, or 35 mg BID, or any amount in between. In some embodiments, subjects have severe renal impairment at baseline, and the prescribed daily effective dose of voclosporine is approximately 15.8 mg BID.

[0308] In some embodiments, the subject has moderate hepatic impairment, and the prescribed daily effective dose of voclosporine is one of approximately 2, 5, 7.9, 10, 12, 15, 15.8, 20, 23.7, 25, 28, 30, 31.6, or 35 mg BID, or any amount in between. In some embodiments, the subject has moderate hepatic impairment, and the prescribed daily effective dose of voclosporine is approximately 15.8 mg BID.

[0309] In some embodiments, voclosporine is administered over a long period of time. In some embodiments, voclosporine is administered once or more times. In some embodiments, voclosporine administration includes an initial dose (or first dose) and one or more subsequent doses.

[0310] In some embodiments of the methods and uses provided herein, voclosporine is administered four times daily, three times daily, twice daily (BID), or once daily. In some embodiments, voclosporine is administered four times daily. In some embodiments, voclosporine is administered three times daily. In some embodiments, voclosporine is administered twice daily (BID). In some embodiments, voclosporine is administered once daily.

[0311] In some embodiments, voclosporine is administered at a constant dose throughout the voclosporine treatment period. In some embodiments, the dose of voclosporine may vary during the voclosporine treatment period, for example, based on an assessment of the therapy.

[0312] In some aspects, the daily dose of voclosporine is approximately 1 mg to 250 mg, approximately 5 mg to 250 mg, approximately 10 mg to 250 mg, approximately 50 mg to 250 mg, approximately 100 mg to 250 mg, approximately 150 mg to 250 mg, approximately 200 mg to 250 mg, 1 mg to 200 mg, approximately 5 mg to 200 mg, approximately 10 mg to 200 mg, approximately 50 mg to 200 mg, approximately 100 mg to 250 mg. The dosages are 200mg, approximately 150mg to 200mg, approximately 1mg to 150mg, approximately 5mg to 150mg, approximately 10mg to 150mg, approximately 50mg to 150mg, approximately 100mg to 150mg, approximately 1mg to 100mg, approximately 5mg to 100mg, approximately 10mg to 100mg, approximately 50mg to 100mg, approximately 1mg to 50mg, approximately 5mg to 50mg, or approximately 10mg to 50mg. In some embodiments, the daily dose of voclosporine is approximately 1 mg, 5 mg, 10 mg, 20 mg, 30 mg, 40 mg, 50 mg, 60 mg, 70 mg, 80 mg, 90 mg, 100 mg, 110 mg, 120 mg, 130 mg, 140 mg, 150 mg, 160 mg, 170 mg, 180 mg, 190 mg, 200 mg, 210 mg, 220 mg, 230 mg, 240 mg, or 250 mg. In some embodiments, the daily dose of voclosporine 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.

[0313] In some embodiments, the dose of voclosporine is approximately 0.1 mg / kg / day to approximately 2 mg / kg / day, approximately 0.5 mg / kg / day to approximately 2 mg / kg / day, approximately 1 mg / kg / day to approximately 2 mg / kg / day, approximately 1.5 mg / kg / day to approximately 2 mg / kg / day, approximately 0.1 mg / kg / day to approximately 1.5 mg / kg / day, approximately 0.5 mg / kg / day to approximately 1.5 mg / kg / day, approximately 1 mg / kg / day to approximately 1.5 mg / kg / day, approximately 0.1 mg / kg / day to approximately 1.0 mg / kg / day, approximately 0.5 mg / kg / day to approximately 1.0 mg / kg / day, or approximately 0.1 mg / kg / day to approximately 0.5 mg / kg / day. In some embodiments, the dose of voclosporine is approximately 0.1, 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 mg / kg / day. In some embodiments, the dose of voclosporine 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.

[0314] In some embodiments, preferred doses of voclosporine are in increments of approximately 7.9 mg. In some embodiments, doses of voclosporine are approximately 7.9 mg QD, approximately 15.8 mg QD, approximately 23.7 mg QD, approximately 31.6 mg QD, approximately 39.5 mg QD, approximately 47.4 mg QD, approximately 55.3 mg QD, approximately 63.2 mg QD, approximately 71.1 mg QD, approximately 79.0 mg QD, approximately 86.9 mg QD, approximately 94.8 mg QD, approximately 102.7 mg QD, or approximately 110.6 mg QD. In some embodiments, doses of voclosporine are approximately 7.9 mg BID, approximately 15.8 mg BID, approximately 23.7 mg BID, approximately 31.6 mg BID, approximately 39.5 mg BID, approximately 47.4 mg BID, or approximately 55.3 mg BID. In some embodiments, the dose of voclosporine is approximately 7.9 mg BID. In some embodiments, the dose of voclosporine is approximately 15.8 mg BID.

[0315] In some embodiments, preferred doses of voclosporine are in increments of 7.9 mg, such as 39.5 mg, 31.6 mg, 23.7 mg, 15.8 mg, or 7.9 mg. Lower doses show superior results compared to higher doses of 39.5 mg in each of such doses administered twice daily. Low doses of 15.8 mg or 7.9 mg twice daily are effective. In some embodiments, the dose of voclosporine is approximately 23.7 mg BID.

[0316] The indicated dosage, for example 23.7 mg, may typically have a slight variation of ±10%, or alternatively, a slight variation of 21 mg to 26 mg BID for 23.7 mg. This is due to manufacturing variability, and the ideal dosage is the specified dose, i.e., 23.7 mg BID. Similar variations apply to alternative dosages and differential adjustments.

[0317] In some embodiments, the trough blood level is approximately 25–60 ng / mL. In some embodiments, the trough blood level is approximately 25, 30, 35, 40, 45, 50, 55, or 60 ng / mL.

[0318] In some embodiments, the therapeutically effective dose of voclosporine is equivalent to, can be extrapolated to, can achieve, or can be achieved as the Cmax of, a concentration of approximately 0.05 μM to 10 μM, approximately 0.1 μM to 5 μM, approximately 0.2 μM to 2.5 μM, approximately 0.3 μM to 1.0 μM, approximately 0.4 μM to 0.9 μM, approximately 0.5 μM to 0.8 μM, approximately 0.1 μM to 0.5 μM, or approximately 0.2 μM to 0.4 μM. In some embodiments, the therapeutically effective dose of voclosporine is an amount equivalent to, or that can be extrapolated to, or that can be achieved, or that can be achieved as the 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 μM or less. In some embodiments, the therapeutically effective dose of voclosporine is equivalent to, can be extrapolated to, can achieve, or can be achieved as the Cmax of, a concentration of approximately 0.2 μM. In some embodiments, the therapeutically effective dose of voclosporine is equivalent to, can be extrapolated to, can achieve, or can be achieved as the Cmax of, a concentration of approximately 0.3 μM. In some embodiments, the therapeutically effective dose of voclosporine is equivalent to, can be extrapolated to, can achieve, or can be achieved as the Cmax of, a concentration of approximately 0.4 μM. In some embodiments, the therapeutically effective dose of voclosporine is equivalent to, can be extrapolated to, can achieve, or can be achieved as the Cmax of, a concentration of approximately 0.5 μM.

[0319] In some embodiments, voclosporine is administered based on a treatment regimen over the voclosporine treatment period. In some embodiments, the voclosporine treatment regimen further includes assessing the subject's estimated glomerular filtration rate (eGFR) at at least a first and second time point on separate days during the voclosporine treatment period, and if the subject's eGFR falls below a predetermined value by a significant amount between the first and second time points, reducing the daily dose in 7.9 mg BID increments or discontinuing administration of voclosporine to the subject. In some examples, the voclosporine treatment regimen further includes assessing the subject's estimated glomerular filtration rate (eGFR) at at least a first and second time point on separate days during the voclosporine treatment period, and if the subject's eGFR falls below the target percentage between the first and second time points, the method further includes continuing administration of the same predetermined daily dose of voclosporine to the subject.

[0320] In some embodiments, the voclosporine treatment period is at least one of approximately 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 110, 120 weeks, or 130 weeks, or any length in between. In certain embodiments, the voclosporine treatment period is at least approximately 65 weeks. In certain embodiments, the voclosporine treatment period is at least approximately 65 weeks. In some embodiments, the first time point is immediately before the start of voclosporine treatment. In some examples, a given value is approximately 30 to approximately 110 ml / min / 1.73m 2 It is within the range. In some embodiments, the given value is approximately 50 to approximately 90 ml / min / 1.73 m 2 The range is as follows: In some embodiments, the given values ​​are approximately 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, and 100-110 ml / min / 1.73m 2 It is within the range of any one of the following. In some embodiments, the given value is approximately 30, 40, 50, 60, 70, 80, 90, or 100 ml / min / 1.73 m 2It is one of the following. In some embodiments, the given value is approximately 60 ml / min / 1.73 m 2 In some embodiments, the target percentage is in the range of approximately 10% to approximately 60%. In some embodiments, the target percentage is in the range of approximately 20% to approximately 45%. In some embodiments, the target percentage is in the range of any one of the following: approximately 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 embodiments, the target percentage is approximately 20%. In some embodiments, the target percentage is approximately 30%.

[0321] In some embodiments, the voclosporine treatment regimen involves assessing the subject's estimated glomerular filtration rate (eGFR) at at least two time points on separate days during the voclosporine treatment period, and determining when the subject's eGFR has decreased by more than 20% between the first and second time points to 60 ml / min / 1.73m². 2 If the dose falls below a certain level, the method further includes reducing the daily dose in 7.9 mg BID increments or discontinuing administration of voclosporine to the subject. In some cases, the voclosporine treatment regimen further includes assessing the subject's estimated glomerular filtration rate (eGFR) at at least a first and second time point on separate days during the voclosporine treatment period, and if the subject's eGFR falls by less than 20% between the first and second time points, the method includes continuing administration of the same predetermined daily dose of voclosporine to the subject.

[0322] In some embodiments, the treatment regimen includes assessing the subject's estimated glomerular filtration rate (eGFR) at at least a first and second time point on separate days during the voclosporine treatment period, the first time point being immediately before the initiation of voclosporine treatment. In some embodiments, the treatment regimen further includes assessing the subject's eGFR every two weeks after the initiation of voclosporine treatment. In some embodiments, the treatment regimen includes assessing the subject's eGFR every two weeks for the first month after the initiation of voclosporine treatment, and then every four weeks thereafter. In some embodiments, if the subject's eGFR falls significantly below a target percentage at any assessment after the initiation of voclosporine treatment and falls below a predetermined value, the treatment regimen includes reducing the daily dose in 7.9 mg BID increments or discontinuing voclosporine administration to the subject.

[0323] In some embodiments, the treatment regimen includes assessing the subject's eGFR at at least a first and second time point on separate days during the voclosporine treatment period, the first time point being immediately before the initiation of voclosporine treatment. In some embodiments, if the subject's eGFR, in the assessment after the initiation of voclosporine treatment, has fallen significantly below a target percentage compared to the eGFR at the first time point and is below a predetermined value, the treatment regimen includes reducing the daily dose by 7.9 mg BID. In some embodiments, if the subject's eGFR, in the assessment after the initiation of voclosporine treatment, has fallen significantly below a target percentage compared to the eGFR at the first time point and is below a predetermined value, the daily dose is reduced by 7.9 mg BID, and the treatment regimen includes assessing the subject's eGFR two weeks after the dose reduction, and further includes a second dose reduction of 7.9 mg BID if the subject's eGFR, in the assessment two weeks after the first dose reduction, has fallen significantly below a target percentage compared to the eGFR at the first time point and is below a predetermined value. In some embodiments, the treatment regimen includes one or more dose reductions, and the treatment regimen includes evaluating the subject's eGFR every two weeks after one or more dose reductions, and if the subject's eGFR has decreased by less than a target percentage compared to the eGFR at the first time point, the daily dose is increased by 7.9 mg BID for each eGFR evaluation. In some embodiments, the dose increase does not result in the dose exceeding the initial predetermined dose. In some examples, the predetermined value is approximately 30 to approximately 110 ml / min / 1.73 m 2 It is within the range. In some embodiments, the given value is approximately 50 to approximately 90 ml / min / 1.73 m 2 The range is as follows: In some embodiments, the given values ​​are approximately 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, and 100-110 ml / min / 1.73m 2 It is within the range of any one of the following. In some embodiments, the given value is approximately 30, 40, 50, 60, 70, 80, 90, or 100 ml / min / 1.73 m 2 It is one of the following. In some embodiments, the given value is approximately 60 ml / min / 1.73 m 2In some embodiments, the target percentage is in the range of approximately 10% to approximately 60%. In some embodiments, the target percentage is in the range of approximately 10% to approximately 45%. In some embodiments, the target percentage is in the range of any one of the following: approximately 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 embodiments, the target percentage is approximately 20%.

[0324] In some aspects, the subject's eGFR decreased by approximately 20% to 30% compared to the eGFR at the first time point when evaluated after the initiation of voclosporine treatment, reaching 60 ml / min / 1.73 m². 2 If the dose falls below 60 ml / min / 1.73 m³, the treatment regimen includes reducing the daily dose by 7.9 mg BID. In some embodiments, the subject's eGFR is approximately 20% to 30% lower at the time of evaluation after initiation of voclosporine treatment compared to the eGFR at the first time point, with a flow rate of 60 ml / min / 1.73 m³. 2 The daily dose was reduced to less than 7.9 mg BID, and the treatment regimen included evaluating the subject's eGFR 2 weeks after the dose reduction, and the subject's eGFR, at the evaluation 2 weeks after the first dose reduction, was lower than 20% compared to the eGFR at the first time point, at 60 ml / min / 1.73 m 2 If the eGFR falls below a certain level, the regimen further includes a second reduction of 7.9 mg BID per day. In some embodiments, the treatment regimen includes one or more dose reductions, and the treatment regimen includes evaluating the subject's eGFR every two weeks after one or more dose reductions, and if the subject's eGFR has decreased by less than 20% compared to the eGFR at the first time point, the regimen includes increasing the daily dose by 7.9 mg BID for each eGFR evaluation. In some embodiments, the dose increase does not result in the dose exceeding the initial predetermined dose.

[0325] In some embodiments, the treatment regimen includes evaluating the subject's eGFR at at least a first and second time point on separate days during the voclosporine treatment period, the first time point being immediately before the initiation of voclosporine treatment. In some embodiments, if the subject's eGFR has decreased by at least a first target percentage compared to the eGFR at the first time point and fallen below a predetermined value at any evaluation after the initiation of voclosporine treatment, the treatment regimen includes discontinuing administration of voclosporine to the subject. In some embodiments, if the subject's eGFR has decreased by at least a target percentage compared to the eGFR at the first time point and fallen below a predetermined value at an evaluation after the initiation of voclosporine treatment, and administration of voclosporine to the subject has been discontinued, the treatment regimen includes evaluating the subject's eGFR two weeks after discontinuation, and further includes resuming administration at the initial predetermined dose if the subject's eGFR has decreased by less than a second target percentage compared to the eGFR at the evaluation two weeks after discontinuation of voclosporine administration. In some embodiments, the predetermined value is approximately 50 to approximately 90 ml / min / 1.73 m 2 The range is as follows: In some embodiments, the given values ​​are approximately 30-40, 40-50, 50-60, 60-70, 70-80, 80-90, 90-100, and 100-110 ml / min / 1.73m 2 It is within the range of any one of the following. In some embodiments, the given value is approximately 30, 40, 50, 60, 70, 80, 90, or 100 ml / min / 1.73 m 2 It is one of the following. In some embodiments, the given value is approximately 60 ml / min / 1.73 m 2In some embodiments, the first target % is in the range of approximately 10% to approximately 60%. In some embodiments, the first target % is in the range of approximately 20% to approximately 45%. In some embodiments, the first target % is in the range of any one of approximately 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 embodiments, the first target % is approximately 30%. In some embodiments, the second target % is in the range of approximately 10% to approximately 60%. In some embodiments, the second target % is in the range of approximately 10% to approximately 45%. In some embodiments, the second target percentage is within one of the following ranges: approximately 10%–20%, 20%–30%, 30–35%, 35%–40%, 40%–45%, 45%–50%, 50%–55%, and 55%–60%. In some embodiments, the second target percentage is approximately 20%.

[0326] In some embodiments, the subject's eGFR decreased by 30% or more compared to the eGFR at the first time point in any evaluation after the initiation of voclosporine treatment, reaching 60 ml / min / 1.73 m². 2 If the eGFR falls below 60 ml / min / 1.73m², the treatment regimen includes discontinuing voclosporine administration to the subject. In some embodiments, the subject's eGFR is 30% or more lower than the eGFR at the first time point in the evaluation after the initiation of voclosporine treatment and is 60 ml / min / 1.73m². 2 If the eGFR falls below a certain level, administration of voclosporine to the subject is discontinued, and the treatment regimen includes evaluating the subject's eGFR two weeks after discontinuation of administration, and further includes restarting administration at the initial prescribed dose if the subject's eGFR, at the evaluation two weeks after discontinuation of voclosporine administration, has decreased by less than 20% compared to the eGFR at the first time point.

[0327] An exemplary treatment regimen for voclosporine involves measuring eGFR at a second time point, immediately before and at least one day after the first dose of voclosporine, and (i) The subject's eGFR has decreased by 30% or more between the first and second time points, reaching 60 mL / min / 1.73 m². 2If the value falls below a certain level, administration of voclosporine to the subject should be stopped or the dose reduced. (ii) The subject's eGFR decreased by 20% to 30% between the first and second time points, reaching 60 ml / min / 1.73 m². 2 If the value falls below a certain level, administer the reduced dose of voclosporine to the affected area. (iii) If the subject's eGFR decreases by 20% or less between the first time point and the second time point, the administration of the same prescribed daily dose of voclosporine to the subject shall be continued.

[0328] In some aspects, before administering the voclosporine treatment regimen to a subject, (a) the subject's urinary protein-creatinine ratio (UPCR) is determined to be greater than 1 mg / mg as measured by first morning urine or 24-hour urine, and (b) the subject's urinary protein-creatinine ratio is 45 ml / min / 1.73 m³ as measured by the formula of the Collaborative Study of Chronic Kidney Disease Epidemiology (CKD-EP1). 2 The further includes identifying a subject as suitable for a treatment regimen by determining that they have an eGFR greater than 1.5 mg / mg, and if conditions (a) and (b) are met, the subject is identified as suitable for a treatment regimen. In some embodiments, the treatment regimen includes determining that the subject's urinary protein-creatinine ratio (UPCR) is greater than 1.5 mg / mg as measured in first morning urine or 24-hour urine.

[0329] In some embodiments, one or more doses of voclosporine are administered to the subject. In some embodiments, one or more doses of a conventional CNI, such as cyclosporine, tacrolimus, or a derivative thereof, have been previously administered to the subject as a first CNI. In some embodiments, the first of one or more doses of voclosporine is administered after the first of one or more doses of the first CNI, such as cyclosporine, tacrolimus, or a derivative thereof. In some embodiments, administration of the first CNI is discontinued and the subject is administered voclosporine. In some embodiments, the subject requiring CNI therapy switches the CNI from a conventional CNI (e.g., cyclosporine, tacrolimus, or a derivative thereof) to voclosporine.

[0330] In some embodiments, the planned voclosporine treatment period begins after the first CNI treatment period. In some embodiments, the planned voclosporine treatment period begins after the completion of the first CNI treatment period or after discontinuation of the first CNI.

[0331] In some embodiments, the planned duration of voclosporine treatment is approximately 10–100 weeks, 10–90 weeks, 10–80 weeks, 10–70 weeks, 10–60 weeks, 10–50 weeks, 10–40 weeks, 10–30 weeks, or 10–20 weeks. In some embodiments, the planned duration of voclosporine treatment is at least approximately 24 weeks, 36 weeks, 48 ​​weeks, 52 weeks, 60 weeks, 72 weeks, 84 weeks, or 96 weeks, or longer. In some embodiments, the planned duration of voclosporine treatment is at least approximately 24 weeks. In some embodiments, the planned duration of voclosporine treatment is at least approximately 48 weeks. In some embodiments, the planned duration of voclosporine treatment is at least approximately 52 weeks. In some embodiments, the planned duration of voclosporine treatment is at least approximately 18 months. In some embodiments, the planned duration of voclosporine treatment is at least approximately 24 months. In some embodiments, the planned duration of voclosporine treatment is at least approximately 36 months. In some embodiments, the planned duration of voclosporine treatment is at least approximately 48 months.

[0332] C. Route of administration In some embodiments of the methods and uses disclosed herein, voclosporine may be administered in any preferred form and by any preferred route, such as intra-intestinal administration (e.g., oral administration, sublingual administration, or rectal administration) or parenteral administration (e.g., intravenous injection, intramuscular injection, subcutaneous injection, intravenous infusion, or inhalation / blow-in), providing a sufficient level of voclosporine.

[0333] In some embodiments, voclosporine is administered intraintestinally. Exemplary routes of intraintestinal administration include, but are not limited to, oral administration, sublingual administration, and rectal administration (e.g., via the rectum). In some embodiments, the intraintestinal administration includes oral administration. In some embodiments, the intraintestinal administration includes sublingual administration. In some embodiments, the intraintestinal administration includes rectal administration.

[0334] In some embodiments, voclosporine is administered by parenteral administration. Exemplary routes of parenteral administration include, but are not limited to, intravenous injection, intramuscular injection, subcutaneous injection, intravenous infusion, and inhalation / blow-in.

[0335] In some embodiments, voclosporine is administered by inhalation or inhalation. Exemplary types of preparations for inhalation and / or inhalation include, but are not limited to, sprays, aerosols, mists, capsules, powders, or cartridges for use with inhalers or inhalers, and solutions / suspensions for spraying. In some embodiments, voclosporine is administered in the form of an aerosol, spray, mist, or powder. In some embodiments, voclosporine is administered in the form of an aerosol. Examples of various types of devices for administration by inhalation or inhalation include, but are not limited to, nebulizers, medium-dose inhalers (MDIs), and dry powder inhalers.

[0336] D. Additional therapeutic agents In some embodiments, the method or treatment also includes administering a therapeutically effective amount of an additional therapeutic agent. In some embodiments, the method also includes administering a therapeutically effective amount of an additional therapeutic agent. In some aspects, the additional therapeutic agent includes a basic immunosuppressive therapy such as mycophenolate mofetil (MMF) or one or more corticosteroids.

[0337] In some embodiments, the method or use further comprises administering an effective amount of mycophenolate mofetil (MMF) to the subject. In some embodiments, the method or use further comprises administering an effective amount of corticosteroid to the subject.

[0338] In some embodiments, in addition to voclosporine, a certain dose of MMF and a decreasing dose of corticosteroid are also administered. In some embodiments, the exemplary dose of MMF includes 2 g / day, and the exemplary dose of oral corticosteroid includes a daily dose that decreases from 20-25 mg / day to 2.5 mg / day over 16 weeks.

[0339] For example, with regard to corticosteroids, subjects weighing 45 kg or more may receive 0.5 g of methylprednisolone intravenously on days 1 and 2 of the study, followed by oral corticosteroid therapy starting on day 3. Subjects weighing less than 45 kg will receive only half of these doses.

[0340] For oral prednisone, exemplary starting doses for oral administration include 20 mg / day for subjects weighing less than 45 kg and 25 mg / day for subjects weighing 45 kg or more. Exemplary administration schedules for corticosteroids are shown in Tables 2 and 3 below. [Table 2] [Table 3]

[0341] Voclosporine is a sensitive CYP3A4 substrate. Co-administration with potent or moderate CYP3A4 inhibitors increases voclosporine exposure. In some embodiments, voclosporine C maxAnd / or AUC increases in subjects receiving potent CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin) or moderate CYP3A4 inhibitors (e.g., verapamil, fluconazole, diltiazem) compared to corresponding subjects not receiving such CYP3A4 inhibitors. In some embodiments, voclosporine C max In subjects receiving a potent or moderate CYP3A4 inhibitor, the voclosporine AUC increases by approximately 1.1 times, 1.2 times, 1.4 times, 1.6 times, 1.8 times, 2.0 times, 2.2 times, 2.4 times, 2.6 times, 2.8 times, 3.0 times, 4.0 times, 5.0 times, 10.0 times, or more, compared to a corresponding subject not receiving such a CYP3A4 inhibitor. In some embodiments, the voclosporine AUC increases by approximately 2.0 times, 2.2 times, 2.4 times, 2.6 times, 2.8 times, 3.0 times, 3.0 times, 3.2 times, 3.4 times, 3.6 times, 3.8 times, 4.0 times, 5.0 times, 10.0 times, or more, compared to a corresponding subject not receiving such a CYP3A4 inhibitor.

[0342] IV. Definition As used herein and in the appended claims, the singular forms "a," "an," and "the" include the plural form unless otherwise explicitly stated in the context.

[0343] Where used herein, unless otherwise specified, the terms “about” and “approximately” when used in relation to dosage or quantity intend to mean a dosage or quantity of no more than 10%, 5%, 4%, 3%, 2%, 1%, or 0.5% of the specified dosage or quantity.

[0344] As used herein, “pharmaceutically acceptable” means a material that is not biologically or otherwise undesirable, for example, that can be incorporated into a pharmaceutical composition administered to a patient without causing a significant undesirable biological effect or adversely interacting with any of the other components of the composition containing it. Pharmacologically acceptable carriers or excipients preferably meet the requirements for toxicity and manufacturing testing and / or are listed in the Inactive Ingredient Guide prepared by the U.S. Food and Drug Administration.

[0345] The term "pharmaceutically acceptable salt" means any salt of any of the compounds herein that is known to be non-toxic and is commonly used in pharmaceutical literature. In some embodiments, pharmaceutically acceptable salts of compounds retain the biological efficacy 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 using inorganic and organic acids. Examples of inorganic acids from which salts can be derived include 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-hydroxyethylsulfonic acid, p-toluenesulfonic acid, stearic acid, and salicylic acid. Pharmaceutically acceptable base addition salts can be formed using 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 salts, potassium salts, sodium salts, calcium salts, and magnesium salts.

[0346] When the compounds described herein are obtained as acid addition salts, the free base can be obtained by basicizing a solution of the acid salt. Conversely, when the compound is a free base, the addition salt, in particular 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, following conventional procedures for preparing acid addition salts from basic compounds (see, for example, Berge et al., Pharmaceutical Salts, J. Pharmaceutical Sciences, January, 1977, 66(1), 1-19). Those skilled in the art will recognize the various synthetic methods that can be used to prepare pharmaceutically acceptable addition salts.

[0347] As used herein, “therapeutic dose” refers to the amount that produces a desired pharmacological and / or physiological effect on the condition in question. This effect may be prophylactic, in that it completely or partially prevents the condition or its symptoms, and / or therapeutic, in that it partially or completely cures the condition and / or any side effects resulting from it.

[0348] The terms “to treat,” “to treat,” and “treatment” refer to an approach to obtain an outcome, including beneficial or desired clinical outcomes. Beneficial or desired outcomes include, but are not limited to, one or more of the following: reducing one or more symptoms of a disease or disorder; reducing the severity of a disease or disorder; stabilizing a disease or disorder (e.g., preventing or delaying the worsening of a disease or disorder); delaying the onset or recurrence of a disease or disorder; delaying or slowing the progression of a disease or disorder; improving the state of a disease or disorder; providing remission (partial or complete) of a disease or disorder; reducing the dose of one or more other medications required to treat a disease or disorder; enhancing the effect of another medication used to treat a disease or disorder; delaying the progression of a disease or disorder; improving quality of life; and / or extending the patient’s survival. Similarly, “treatment” includes mitigating the pathological consequences of a disease or disorder. The methods of this disclosure aim to achieve any one or more of these forms of treatment.

[0349] The term "subject" refers to animals including, but not limited to, primates (e.g., humans), monkeys, cattle, pigs, sheep, goats, horses, dogs, cats, rabbits, rats, or mice. In this specification, the terms "subject" and "patient" are used synonymously to refer to mammalian subjects such as humans.

[0350] V. Exemplary Embodiments The embodiments provided include the following:

[0351] 1. A method of treatment, wherein the method is (a) Selecting subjects who have previously received a first calcineurin inhibitor (CNI) for immunosuppression for at least 30 days, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof. (b) The method comprising administering voclosporine to the selected subject.

[0352] 2. A method of treatment comprising administering voclosporine to a subject who has previously received a first calcineurin inhibitor (CNI) for immunosuppression for at least 30 days, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0353] 3. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects who have previously received a first calcineurin inhibitor (CNI) for immunosuppression for at least 30 days, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0354] 4. The method according to any one of Embodiments 1 to 3, further comprising performing one or more renal biopsies on the subject.

[0355] 5. The method according to Embodiment 4, wherein one or more indicators of drug-induced nephrotoxicity are evaluated based on one or more renal biopsies.

[0356] 6. A method for reducing drug-induced nephrotoxicity, wherein the method is (a) Selecting a subject who exhibits one or more indicators of drug-induced nephrotoxicity after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof. (b) The method comprising administering voclosporine to the selected subject.

[0357] 7. A method for mitigating drug-induced nephrotoxicity, the method comprising administering voclosporine to a subject exhibiting one or more indicators of drug-induced nephrotoxicity after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0358] 8. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects exhibiting one or more indicators of drug-induced nephrotoxicity after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0359] 9. The method according to any one of embodiments 6 to 8, wherein one or more indicators of drug-induced nephrotoxicity are evaluated based on one or more renal biopsies.

[0360] 10. A method for alleviating drug-induced tubular dysfunction, wherein the method is (a) Selecting a subject who exhibits one or more indicators of drug-induced tubular dysfunction after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof. (b) The method comprising administering voclosporine to the selected subject.

[0361] 11. A method for alleviating drug-induced tubular dysfunction, the method comprising administering voclosporine to a subject exhibiting one or more indicators of drug-induced tubular dysfunction after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0362] 12. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects exhibiting one or more indicators of drug-induced tubular dysfunction after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0363] 13. The method according to any one of embodiments 10 to 12, wherein the drug-induced tubular dysfunction includes drug-induced hypercalcemia.

[0364] 14. A method for reducing drug-induced hypercalcemia, wherein the method is (a) Selecting a subject who exhibits one or more indicators of drug-induced hypercalcemia after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof. (b) The method comprising administering voclosporine to the selected subject.

[0365] 15. A method for alleviating drug-induced hypercalcemia, the method comprising administering voclosporine to a subject exhibiting one or more indicators of drug-induced hypercalcemia after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0366] 16. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects exhibiting one or more indicators of drug-induced hypercalcemia after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0367] 17. The method according to any one of Embodiments 1 to 16, wherein the subject is selected for administration of voclosporine if the subject shows an increase of 10% or more in the fractional calcium excretion rate evaluated after receiving the first CNI compared to the baseline fractional calcium excretion rate evaluated before receiving the first CNI.

[0368] 18. The method according to any one of Embodiments 1 to 17, wherein the subject is selected for administration of voclosporine if the subject shows an increase of 1.2 times or more in the magnesium fractional excretion rate evaluated after receiving the first CNI compared to the baseline magnesium fractional excretion rate evaluated before receiving the first CNI.

[0369] 19. The method according to any one of Embodiments 1 to 18, wherein the subject is selected for administration of voclosporine if the subject shows a decrease of 33% or more in creatinine-normalized urinary epidermal growth factor (uEGF / Cr) evaluated after receiving the first CNI compared to baseline uEGF / Cr evaluated before receiving the first CNI.

[0370] 20. The method according to any one of Embodiments 1 to 19, wherein the subject is selected for administration of voclosporine if the subject shows a decrease of more than twofold in the level of calbindin-D28K assessed after receiving the first CNI compared to the baseline level of calbindin-D28K assessed before receiving the first CNI.

[0371] 21. The method according to any one of Embodiments 1 to 18, wherein the subject is selected for administration of voclosporine if the subject shows a decrease of 1.5 times or more in the level of sodium chloride cotransporter (NCC) assessed after receiving the first CNI compared to the baseline level of NCC assessed before receiving the first CNI.

[0372] 22. The method according to any one of Embodiments 1 to 21, wherein the subject is selected for administration of voclosporine if the expression level of one or more genes selected from the group consisting of Slc12a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8a1, and Calb1, as evaluated after receiving the first CNI, shows a decrease of 30% or more compared to the baseline expression level of each of the one or more genes evaluated before receiving the first CNI.

[0373] 23. The method according to any one of Embodiments 1 to 22, wherein if the subject exhibits hypercalciuria, the subject is selected for administration of voclosporine.

[0374] 24. The method according to any one of embodiments 10 to 12, wherein the drug-induced tubular dysfunction includes hyperkalemia.

[0375] 25. The method according to Embodiment 24, wherein the hyperkalemia is identified by a serum potassium level greater than 5 mmol / L.

[0376] 26. The method according to any one of embodiments 10 to 12, wherein the drug-induced tubular dysfunction includes hypomagnesemia.

[0377] 27. The method according to Embodiment 26, wherein the hypomagnesemia is identified by a serum magnesium level of less than 1.4 mg / dL.

[0378] 28. The method according to any one of embodiments 10 to 12, wherein the drug-induced tubular dysfunction includes hypophosphatemia.

[0379] 29. A method of treatment, wherein the method is (a) Selecting subjects who show an increase of 10% or more in the fractional calcium excretion rate evaluated after receiving a first calcineurin inhibitor (CNI) for immunosuppression compared to the baseline fractional calcium excretion rate evaluated before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof. (b) The method comprising administering voclosporine to the selected subject.

[0380] 30. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects that show an increase of 10% or more in the fractional calcium excretion rate evaluated after receiving a first calcineurin inhibitor (CNI) for immunosuppression compared to a baseline fractional calcium excretion rate evaluated before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0381] 31. The method according to any one of embodiments 17 to 30, wherein the subject is selected for treatment if the subject shows an increase of 20% or more in the calcium fraction excretion rate after receiving the first CNI.

[0382] 32. The method according to any one of embodiments 17 to 31, wherein the subject is selected for treatment if the subject shows a twofold or greater increase in calcium fraction excretion rate after receiving the first CNI.

[0383] 33. The method according to any one of embodiments 17 to 32, wherein the subject is selected for treatment if the subject shows an increase of three times or more in the calcium fraction excretion rate after receiving the first CNI.

[0384] 34. A method of treatment, wherein the method is (a) Selecting subjects who show a 1.2-fold or greater increase in magnesium fractional excretion rate, as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, compared to a baseline magnesium fractional excretion rate assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof. (b) The method comprising administering voclosporine to the selected subject.

[0385] 35. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects that show an increase of 1.2 times or more in the magnesium fractional excretion rate evaluated after receiving a first calcineurin inhibitor (CNI) for immunosuppression compared to a baseline magnesium fractional excretion rate evaluated before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0386] 36. The method according to any one of embodiments 18 to 35, wherein the subject is selected for treatment if the subject shows an increase of 1.5 times or more in the magnesium fractional excretion rate after receiving the first CNI.

[0387] 37. A method of treatment, wherein the method is (a) Selecting subjects who, after receiving a first calcineurin inhibitor (CNI) for immunosuppression, show a decrease of 33% or more in creatinine-normalized urinary epidermal growth factor (uEGF / Cr) compared to baseline uEGF / Cr assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof. (b) The method comprising administering voclosporine to the selected subject.

[0388] 38. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects showing a decrease of 33% or more in creatinine-normalized urinary epidermal growth factor (uEGF / Cr) evaluated after receiving a first calcineurin inhibitor (CNI) for immunosuppression, compared to baseline uEGF / Cr evaluated before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0389] 39. The method according to any one of embodiments 19 to 38, wherein if the subject shows a decrease of 40% or more in uEGF / Cr after receiving the first CNI, the subject is selected for treatment.

[0390] 40. A method of treatment, wherein the method is (a) Selecting subjects whose calbindin-D28K levels, as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, show a decrease of 2-fold or more compared to baseline levels of calbindin-D28K assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof. (b) The method comprising administering voclosporine to the selected subject.

[0391] 41. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects who show a twofold or greater decrease in calbindin-D28K levels assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression compared to baseline levels of calbindin-D28K assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0392] 42. The method according to any one of embodiments 20 to 41, wherein if the subject shows a threefold or greater increase in the level of calbindin-D28K after receiving the first CNI, the subject is selected for treatment.

[0393] 43. A method of treatment, wherein the method is (a) Selecting subjects who, after receiving a first calcineurin inhibitor (CNI) for immunosuppression, show a decrease of 1.5 times or more in sodium chloride cotransporter (NCC) levels compared to baseline NCC levels assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or derivatives thereof. (b) The method comprising administering voclosporine to the selected subject.

[0394] 44. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects who show a decrease of 1.5 times or more in sodium chloride cotransporter (NCC) levels assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression compared to baseline levels of NCC assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

[0395] 45. The method according to any one of embodiments 21 to 44, wherein if the subject shows an increase of more than twice the level of NCC after receiving the first CNI, the subject is selected for treatment.

[0396] 46. ​​A method of treatment, wherein the method is (a) Selecting subjects whose expression levels, as evaluated after receiving a first calcineurin inhibitor (CNI) for immunosuppression, are 30% or more lower than the baseline expression levels of the one or more genes selected from the group consisting of Slc12a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8a1, and Calb1, compared to the ...

Claims

1. A method of treatment, wherein the method is (a) Selecting subjects who have previously received a first calcineurin inhibitor (CNI) for immunosuppression for at least 30 days, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof. (b) The method comprising administering voclosporine to the selected subject.

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

3. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects who have previously received a first calcineurin inhibitor (CNI) for immunosuppression for at least 30 days, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

4. The method according to any one of claims 1 to 3, further comprising performing one or more renal biopsies on the subject.

5. The method according to claim 4, wherein one or more indicators of drug-induced nephrotoxicity are evaluated based on one or more renal biopsies.

6. A method for reducing drug-induced nephrotoxicity, wherein the method is (a) Selecting a subject who exhibits one or more indicators of drug-induced nephrotoxicity after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof. (b) The method comprising administering voclosporine to the selected subject.

7. A method for mitigating drug-induced nephrotoxicity, the method comprising administering voclosporine to a subject exhibiting one or more indicators of drug-induced nephrotoxicity after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

8. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects exhibiting one or more indicators of drug-induced nephrotoxicity after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

9. The method according to any one of claims 6 to 8, wherein one or more indicators of drug-induced nephrotoxicity are evaluated based on one or more renal biopsies.

10. A method for alleviating drug-induced tubular dysfunction, wherein the method is (a) Selecting subjects who exhibit one or more indicators of drug-induced tubular dysfunction after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof. (b) The method comprising administering voclosporine to the selected subject.

11. A method for alleviating drug-induced tubular dysfunction, the method comprising administering voclosporine to a subject exhibiting one or more indicators of drug-induced tubular dysfunction after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

12. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects exhibiting one or more indicators of drug-induced tubular dysfunction after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

13. The method according to any one of claims 10 to 12, wherein the drug-induced tubular dysfunction includes drug-induced hypercalcemia.

14. A method for reducing drug-induced hypercalcemia, wherein the method is (a) Selecting a subject who exhibits one or more indicators of drug-induced hypercalcemia after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof. (b) The method comprising administering voclosporine to the selected subject.

15. A method for alleviating drug-induced hypercalcemia, the method comprising administering voclosporine to a subject exhibiting one or more indicators of drug-induced hypercalcemia after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

16. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects exhibiting one or more indicators of drug-induced hypercalcemia after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

17. The method according to any one of claims 1 to 16, wherein the subject is selected for administration of voclosporine if the subject shows an increase of 10% or more in the calcium fraction excretion rate evaluated after receiving the first CNI compared to the baseline calcium fraction excretion rate evaluated before receiving the first CNI.

18. The method according to any one of claims 1 to 17, wherein the subject is selected for administration of voclosporine if the subject shows an increase of 1.2 times or more in the magnesium fractional excretion rate evaluated after receiving the first CNI compared with the baseline magnesium fractional excretion rate evaluated before receiving the first CNI.

19. The method according to any one of claims 1 to 18, wherein if the subject shows a decrease of 33% or more compared to baseline uEGF / Cr assessed before receiving the first CNI, based on creatinine-normalized urinary epidermal growth factor (uEGF / Cr) evaluated after receiving the first CNI, the subject is selected for administration of voclosporine.

20. The method according to any one of claims 1 to 19, wherein if the subject shows a decrease of more than twofold in the level of calbindin-D28K assessed after receiving the first CNI compared to the baseline level of calbindin-D28K assessed before receiving the first CNI, the subject is selected for administration of voclosporine.

21. The method according to any one of claims 1 to 18, wherein the subject is selected for administration of voclosporine if the level of sodium chloride cotransporter (NCC) evaluated after receiving the first CNI is 1.5 times or more lower than the baseline level of NCC evaluated before receiving the first CNI.

22. The method according to any one of claims 1 to 21, wherein the subject is selected for administration of voclosporine if the expression level of one or more genes selected from the group consisting of Slc12a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8a1, and Calb1, as evaluated after receiving the first CNI, shows a decrease of 30% or more compared to the baseline expression level of each of the one or more genes evaluated before receiving the first CNI.

23. The method according to any one of claims 1 to 22, wherein if the subject exhibits hypercalciuria, the subject is selected for administration of voclosporine.

24. The method according to any one of claims 10 to 12, wherein the drug-induced tubular dysfunction includes hyperkalemia.

25. The method according to claim 24, wherein the hyperkalemia is identified by a serum potassium level greater than 5 mmol / L.

26. The method according to any one of claims 10 to 12, wherein the drug-induced tubular dysfunction includes hypomagnesemia.

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

28. The method according to any one of claims 10 to 12, wherein the drug-induced tubular dysfunction includes hypophosphatemia.

29. A method of treatment, wherein the method is (a) Selecting subjects who show an increase of 10% or more in the fractional calcium excretion rate evaluated after receiving a first calcineurin inhibitor (CNI) for immunosuppression compared to the baseline fractional calcium excretion rate evaluated before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof. (b) The method comprising administering voclosporine to the selected subject.

30. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects that show an increase of 10% or more in the fractional calcium excretion rate evaluated after receiving a first calcineurin inhibitor (CNI) for immunosuppression compared to a baseline fractional calcium excretion rate evaluated before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

31. The method according to any one of claims 17 to 30, wherein if the subject shows an increase of 20% or more in the calcium fraction excretion rate after receiving the first CNI, the subject is selected for treatment.

32. The method according to any one of claims 17 to 31, wherein if the subject shows a twofold or greater increase in calcium fraction excretion rate after receiving the first CNI, the subject is selected for treatment.

33. The method according to any one of claims 17 to 32, wherein if the subject shows an increase of three times or more in the calcium fraction excretion rate after receiving the first CNI, the subject is selected for treatment.

34. A method of treatment, wherein the method is (a) Selecting subjects whose magnesium fractional excretion rate, as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, shows an increase of 1.2 times or more compared to the baseline magnesium fractional excretion rate assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof. (b) The method comprising administering voclosporine to the selected subject.

35. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects that show an increase of 1.2 times or more in the magnesium fractional excretion rate evaluated after receiving a first calcineurin inhibitor (CNI) for immunosuppression compared to a baseline magnesium fractional excretion rate evaluated before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

36. The method according to any one of claims 18 to 35, wherein if the subject shows an increase of 1.5 times or more in the magnesium fractional excretion rate after receiving the first CNI, the subject is selected for treatment.

37. A method of treatment, wherein the method is (a) Selecting subjects whose creatinine-normalized urinary epidermal growth factor (uEGF / Cr), as evaluated after receiving a first calcineurin inhibitor (CNI) for immunosuppression, shows a decrease of 33% or more compared to baseline uEGF / Cr evaluated before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof. (b) The method comprising administering voclosporine to the selected subject.

38. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects showing a decrease of 33% or more in creatinine-normalized urinary epidermal growth factor (uEGF / Cr) evaluated after receiving a first calcineurin inhibitor (CNI) for immunosuppression, compared to baseline uEGF / Cr evaluated before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

39. The method according to any one of claims 19 to 38, wherein if the subject shows a decrease of 40% or more in uEGF / Cr after receiving the first CNI, the subject is selected for treatment.

40. A method of treatment, wherein the method is (a) Selecting subjects who show a twofold or greater decrease in calbindin-D28K levels assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression compared to baseline levels of calbindin-D28K assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or derivatives thereof. (b) The method comprising administering voclosporine to the selected subject.

41. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects who show a twofold or greater decrease in calbindin-D28K levels assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression compared to baseline levels of calbindin-D28K assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

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

43. A method of treatment, wherein the method is (a) Selecting subjects whose sodium chloride cotransporter (NCC) levels, as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, show a decrease of 1.5 times or more compared to baseline levels of NCCs assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or derivatives thereof. (b) The method comprising administering voclosporine to the selected subject.

44. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects whose sodium chloride cotransporter (NCC) levels, as assessed after receiving a first calcineurin inhibitor (CNI) for immunosuppression, show a decrease of 1.5 times or more compared to baseline levels of NCCs assessed before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

45. The method according to any one of claims 21 to 44, wherein if the subject shows an increase of more than twice the level of NCC after receiving the first CNI, the subject is selected for treatment.

46. A method of treatment, wherein the method is (a) Selecting subjects whose expression levels, as evaluated after receiving a first calcineurin inhibitor (CNI) for immunosuppression, are 30% or more lower than the baseline expression levels of the one or more genes selected from the group consisting of Slc12a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8a1, and Calb1, compared to the baseline expression levels of the one or more genes evaluated before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or derivatives thereof. (b) The method comprising administering voclosporine to the selected subject.

47. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects whose expression levels, as evaluated after receiving a first calcineurin inhibitor (CNI) for immunosuppression, are 30% or more lower than the baseline expression levels of the one or more genes selected from the group consisting of Slc12a3, Trpm6, Cnnm2, Egf, Trpv5, Slc8a1, and Calb1, compared to the baseline expression levels of the one or more genes evaluated before receiving the first CNI, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

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

49. A method for alleviating drug-induced dyslipidemia, wherein the method is (a) Selecting a subject who exhibits one or more indicators of drug-induced dyslipidemia after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof. (b) The method comprising administering voclosporine to the selected subject.

50. A method for alleviating drug-induced dyslipidemia, the method comprising administering voclosporine to a subject exhibiting one or more indicators of drug-induced dyslipidemia after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

51. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects exhibiting one or more indicators of drug-induced dyslipidemia after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

52. The method according to any one of claims 1 to 51, wherein if the subject exhibits hypertriglyceridemia in an evaluation after receiving the first CNI, the subject is selected for administration of voclosporine.

53. The method according to any one of claims 1 to 52, wherein the subject is selected for administration of voclosporine if the subject shows an increase of 30% or more in the level of triacylglycerol (TAG) evaluated after receiving the first CNI compared to the baseline level of TAG evaluated before receiving the first CNI.

54. The method according to any one of claims 1 to 53, wherein the subject is selected for administration of voclosporine if the subject shows an increase of 30% or more in the level of ceramide (CER) evaluated after receiving the first CNI compared to the baseline level of CER evaluated before receiving the first CNI.

55. The method according to any one of claims 1 to 54, wherein if the subject exhibits hypercholesterolemia in an evaluation after receiving the first CNI, the subject is selected for administration of voclosporine.

56. The method according to any one of claims 1 to 55, wherein the subject is selected for administration of voclosporine if the subject shows an increase of 30% or more in the level of low-density lipoprotein (LDL) cholesterol assessed after receiving the first CNI compared to the baseline level of LDL assessed before receiving the first CNI.

57. A method of treatment, wherein the method is (a) Selecting subjects who exhibit a decrease in blood levels of mycophenolate (MPA) after prior treatment with a first calcineurin inhibitor (CNI) in combination with mycophenolate mofetil (MMF) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or derivatives thereof. (b) The method comprising administering voclosporine to the selected subject.

58. A method of treatment comprising administering voclosporine to a subject exhibiting a decrease in blood levels of mycophenolate (MPA) after prior treatment with a first calcineurin inhibitor (CNI) in combination with mycophenolate mofetil (MMF) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

59. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects who exhibit a decrease in blood levels of mycophenolate (MPA) after prior treatment with a first calcineurin inhibitor (CNI) in combination with mycophenolate mofetil (MMF) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

60. The method according to any one of claims 1 to 58, wherein the subject is selected for administration of voclosporine if the subject shows a decrease of 1.5 times or more in the blood level of MPA assessed after receiving the first CNI compared to the baseline blood level of MPA assessed before receiving the first CNI.

61. The blood level of the aforementioned MPA is the highest serum concentration (C ｍａｘ ) or area under the concentration curve (AUC) from 0 to 12 hours ０－１２ The method according to any one of claims 57 to 60, which is determined to be as follows.

62. A method for reducing newly diagnosed diabetes, wherein the method is (a) Selecting subjects who exhibit one or more indicators of new-onset diabetes after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof. (b) The method comprising administering voclosporine to the selected subject.

63. A method for mitigating new-onset diabetes mellitus, the method comprising administering voclosporine to a subject exhibiting one or more indicators of new-onset diabetes mellitus after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

64. A method for selecting subjects for treatment with voclosporine, the method comprising selecting subjects exhibiting one or more indicators of new-onset diabetes after prior treatment with a first calcineurin inhibitor (CNI) for immunosuppression, wherein the first CNI comprises cyclosporine, tacrolimus, or a derivative thereof.

65. The method according to any one of claims 62 to 64, wherein the newly diagnosed diabetes includes newly diagnosed diabetes after transplantation (NODAT).

66. The method according to any one of claims 1 to 65, wherein if the subject exhibits hyperglycemia, the subject is selected for administration of voclosporine.

67. The method according to any one of claims 1 to 66, wherein if the subject exhibits islet cell death, the subject is selected for administration of voclosporine.

68. The method according to any one of claims 1 to 67, wherein the subject is selected for administration of voclosporine if, based on the renal biopsy, the subject exhibits interstitial fibrosis and tubular atrophy observed in more than 5% of the cortical region after receiving the first CNI.

69. The method according to any one of claims 1 to 68, wherein if the subject exhibits arteriolar medial hyalinization after receiving the first CNI based on the renal biopsy, the subject is selected for administration of voclosporine.

70. The method according to claim 69, wherein arteriole medial hyalinization is identified by the replacement of necrotic smooth muscle cells at the outer edge of the afferent arteriole wall with localized, circular, lumpy protein (hyaline) deposits, and / or narrowing of the vascular lumen.

71. The method according to any one of claims 1 to 70, wherein if the subject exhibits glomerular injury, arteriolar medial hyalinization after receiving the first CNI based on the renal biopsy, the subject is selected for administration of voclosporine.

72. The method according to claim 71, wherein glomerular injury is identified by observation of whole-segmental and segmental glomerulosclerosis, tubular atrophy, interstitial fibrosis, and / or arteriosclerosis, and / or a total renal chronicity score > 1.

73. The method according to any one of claims 1 to 72, wherein if the subject exhibits a juxtaglomerular apparatus (JGA) after undergoing the first CNI based on the renal biopsy, the subject is selected for administration of voclosporine.

74. The method according to claim 73, wherein JGA hyperplasia is identified by hypertrophy of components of the juxtaglomerular apparatus, which include one or more of the vascular components, mesangial cell components, and tubular components (macula densa), and / or the presence of intracellular renin granules.

75. The method according to any one of claims 1 to 74, wherein if the subject exhibits tubular microcalcification after receiving the first CNI based on the renal biopsy, the subject is selected for administration of voclosporine.

76. The method according to any one of claims 1 to 75, wherein the subject is selected for administration of voclosporine if, based on the renal biopsy, the subject shows a loss of 10% or more in P-glycoprotein (P-gp) expression evaluated after receiving the first CNI compared to baseline P-gp expression evaluated before receiving the first CNI.

77. The method according to any one of claims 1 to 76, wherein if the subject exhibits a drug-induced nephrotoxicity score of 0 to 3 after undergoing the first CNI based on the renal biopsy, the subject is selected for administration of voclosporine.

78. The method according to any one of claims 1 to 77, wherein if the subject exhibits a Banff score of 0 to 3 after undergoing the first CNI based on the renal biopsy, the subject is selected for administration of voclosporine.

79. The method according to any one of claims 1 to 78, wherein the subject is selected for administration of voclosporine if, based on the renal biopsy, the subject shows an increase in the National Institutes of Health Activity Index (NIH-AI) at the renal biopsy evaluated after receiving the first CNI, compared to a baseline NIH-AI evaluated before receiving the first CNI.

80. The method according to any one of claims 1 to 79, wherein if the subject shows 3 or more NIH-AIs after receiving the first CNI based on the renal biopsy, the subject is selected for administration of voclosporine.

81. The method according to any one of claims 1 to 80, wherein the subject is selected for administration of voclosporine if, based on the renal biopsy, the subject shows an increase of 30% or more in the National Institutes of Health Chronicity Index (NIH-CI) assessed after receiving the first CNI compared to the baseline NIH-CI assessed before receiving the first CNI.

82. The method according to any one of claims 1 to 81, wherein if the subject shows an increase of 40% or more in NIH-CI compared to the baseline NIH-CI based on the renal biopsy, the subject is selected for administration of voclosporine.

83. The method according to any one of claims 1 to 82, wherein if the subject shows 3 or more NIH-CI after receiving the first CNI based on the renal biopsy, the subject is selected for administration of voclosporine.

84. The method according to any one of claims 1 to 83, wherein the subject is selected for administration of voclosporine if, based on the renal biopsy, the subject shows an increase of 10% or more in tubulointerstitial activity index (TIAI) evaluated after receiving the first CNI compared to baseline TIAI.

85. The method according to any one of claims 1 to 84, wherein the subject has previously received cyclosporine, tacrolimus, or a derivative thereof for at least 30 days.

86. The method according to any one of claims 1 to 85, wherein the subject has previously received cyclosporine, tacrolimus, or a 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 according to any one of claims 1 to 86, wherein the first CNI comprises cyclosporine.

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

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

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

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

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

93. The method according to any one of claims 1 to 92, further comprising discontinuing the administration of the first CNI before commencing the administration of the voclosporine.

94. The method according to any one of claims 1 to 93, further comprising administering voclosporine to the selected subject.

95. The method according to any one of claims 1 to 94, wherein the voclosporine is administered in a daily dose of approximately 5 mg BID to approximately 50 mg BID.

96. The method according to any one of claims 1 to 95, wherein the voclosporine is administered in an initial daily dose of approximately 39.5 mg, approximately 31.6 mg, approximately 23.7 mg, approximately 15.8 mg, or approximately 7.9 mg BID.

97. The method according to any one of claims 1 to 96, wherein the voclosporine is administered in an initial daily dose of approximately 39.5 mg.

98. The method according to any one of claims 1 to 96, wherein the voclosporine is administered in an initial daily dose of approximately 23.7 mg.

99. The method according to any one of claims 1 to 96, wherein the voclosporine is administered in an initial daily dose of approximately 15.8 mg.

100. The method according to any one of claims 1 to 99, wherein the voclosporine is administered over a planned voclosporine 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. A method according to any one of claims 1 to 100, (a) Evaluating the estimated glomerular filtration rate (eGFR) of the subject at at least a first and second time point on separate days within the planned treatment period, (b) (i) If the eGFR of the subject falls below a predetermined value by a significant amount between the first time point and the second time point, the daily dose shall be reduced in increments of 7.9 mg BID, or the administration of voclosporine shall be discontinued. (ii) If the eGFR of the subject decreases to less than the target percentage between the first time point and the second time point, the administration of the subject to the same predetermined daily dose of voclosporine shall be continued. The method further includes the method described above.

102. The aforementioned predetermined value is 50 to 90 ml / min / 1.73 m ２ The method according to claim 101, which is within the range.

103. The aforementioned predetermined value is approximately 60 ml / min / 1.73 m ２ The method according to claim 101 or 102.

104. The method according to any one of claims 101 to 103, wherein the target percentage is in the range of 20% to 45%.

105. The method according to any one of claims 101 to 104, wherein the target percentage is approximately 30%.

106. A method according to any one of claims 101 to 105, (i) The eGFR of the subject decreases by more than 30% between the first time point and the second time point to 60 mL / min / 1.73 m ２ If the value falls below a certain level, the administration of voclosporine to the subject shall be stopped. (ii) The eGFR of the subject decreases by 20% to 30% between the first time point and the second time point to 60 ml / min / 1.73 m ２ If the value falls below a certain level, administer the reduced dose of voclosporine to the subject. (iii) The method wherein if the eGFR of the subject decreases by less than 20% between the first time point and the second time point, the administration of the same predetermined daily dose of voclosporine to the subject is continued.

107. The method according to any one of claims 101 to 106, wherein the first time point is immediately before the start of administration of the voclosporine.

108. The method according to any one of claims 101 to 107, wherein the second time point is after the first time point and after the start of administration of voclosporine.

109. The method according to any one of claims 101 to 108, wherein the second time point is eight weeks after the start of administration of voclosporine.

110. The method according to any one of claims 101 to 109, further comprising determining the eGFR of the subject at a third time point, and if it is determined that the eGFR at the third time point differs from the eGFR determined at the first time point by a smaller amount than the target percentage, resuming administration of the predetermined daily dose of voclosporine.

111. A method according to any one of claims 101 to 110, (a) Measure the urinary protein-creatinine ratio (UPCR) of the subject at the first and second time points, and determine whether or not there is a decrease in the UPCR between the first and second time points, (b) If the UPCR of the subject does not show a decrease of at least 25% at the second time point, discontinue administration of voclosporine to the subject. The method further includes the method described above.

112. The method according to any one of claims 101 to 111, further comprising measuring the concentration of C3 or C4 in the subject's blood at the first and second time points, determining whether the concentration of C3 or C4 has normalized at the second time point, and, if normalization of C3 or C4 is found, resuming administration of voclosporine to the subject.

113. The method according to any one of claims 1 to 112, further comprising administering an effective amount of mycophenolate mofetil (MMF) to the subject.

114. The method according to any one of claims 1 to 113, further comprising administering an effective amount of corticosteroid to the subject.

115. The method according to any one of claims 1 to 114, wherein the boclosporine is a mixture of at least 90% E isomer and 10% or less Z isomer.

116. A boxrosporin for use in the method according to any one of claims 1 to 115.

117. Use of voclosporine in the manufacture of a drug according to any one of claims 1 to 115.

118. Use of vocrossporine in the method according to any one of claims 1 to 115.

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