Methods and uses related to administration of voclosporin

Abstract

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

Description

This article provides treatment methods and uses that include administering vorticocephalosporin to subjects who have previously received immunosuppression with a calcineurin inhibitor (CNI) such as cyclosporine, tacrolimus, or a derivative thereof. In some aspects, the methods and uses involve selecting subjects who have previously received immunosuppression with a CNI such as cyclosporine, tacrolimus, or a derivative thereof for administration of vorticocephalosporin. In some aspects, the methods involve treating or mitigating adverse reactions that may be associated with immunosuppression using a CNI such as cyclosporine, tacrolimus, or a derivative thereof. In some aspects, the methods and uses include administering a therapeutically effective amount of vorticocephalosporin to the selected subject. Abstract

Claims

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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