The PROMISE Study: A Phase 2b Multicenter Study of Voclosporin (ISA247) Versus Tacrolimus in De Novo Kidney Transplantation

Busque, Stéphan; Cantarovich, Marcelo; Mulgaonkar, Shamkant; Gaston, Robert S.; Gaber, A. Osama; Mayo, P.R.; Ling, Spencer; Huizinga, Robert B.; Meier-Kriesche, Herwig Ulf

doi:10.1111/j.1600-6143.2011.03763.x

Cited by 81 publications

(70 citation statements)

References 22 publications

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“…Aside from the direct vascular effect on renal blood flow, the potential direct nephrotoxic effects of CNI agents remain an active area of debate and research (21). To address these issues of toxicity and side effect profiles (including post-transplant diabetes), alternative formulations of tacrolimus (extended release) as well as the novel CNI voclosporin have been developed and are approved or in late-phase clinical trials in transplantation (22)(23)(24).…”

Section: Agents Targeting Signalmentioning

confidence: 99%

Immunosuppressive Medications

Wiseman¹

2016

Clinical Journal of the American Society of Nephrology

205

165

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Immunosuppressive agents are commonly used in the nephrologist's practice in the treatment of autoimmune and immune-mediated diseases and transplantation, and they are investigational in the treatment of AKI and ESRD. Drug development has been rapid over the past decades as mechanisms of the immune response have been better defined both by serendipity (the discovery of agents with immunosuppressive activity that led to greater understanding of the immune response) and through mechanistic study (the study of immune deficiencies and autoimmune diseases and the critical pathways or mutations that contribute to disease). Toxicities of early immunosuppressive agents, such as corticosteroids, azathioprine, and cyclophosphamide, stimulated intense investigation for agents with more specificity and less harmful effects. Because the mechanisms of the immune response were better delineated over the past 30 years, this specialty is now bestowed with a multitude of therapeutic options that have reduced rejection rates and improved graft survival in kidney transplantation, provided alternatives to cytotoxic therapy in immune-mediated diseases, and opened new opportunities for intervention in diseases both common (AKI) and rare (atypical hemolytic syndrome). Rather than summarizing clinical indications and clinical trials for all currently available immunosuppressive medications, the purpose of this review is to place these agents into mechanistic context together with a brief discussion of unique features of development and use that are of interest to the nephrologist.

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Section: Agents Targeting Signalmentioning

confidence: 99%

Immunosuppressive Medications

Wiseman¹

2016

Clinical Journal of the American Society of Nephrology

205

165

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“…Based on voclosporin Cmax values obtained from clinical studies in psoriasis patients [18,19] and de novo renal transplant patients [20], the expected [I]/Ki (where [I] is the whole blood concentration of inhibitor for which Cmax is considered an estimate) for voclosporin ranges from 0.125 to 0.216. This suggests that the potential for a clinically relevant drug-drug interaction is between remote ([I]/Ki < 0.1) and possible ([I]/Ki > 1) [3].…”

Section: Discussionmentioning

confidence: 99%

“…Twenty-four subjects were given voclosporin 0.4 mg kg −1 orally Q12H for 20 consecutive days (days [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Subjects were to be given oral ketoconazole 400 mg once daily (QD) for 10 consecutive days (days [11][12][13][14][15][16][17][18][19][20] …”

Section: Ketoconazole Studymentioning

confidence: 99%

Cytochrome P450 3A and P-glycoprotein drug-drug interactions with voclosporin

Ling¹,

Huizinga²,

Mayo³

et al. 2014

Br J Clin Pharmacol

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AIMSVoclosporin is a novel calcineurin inhibitor intended for prevention of organ graft rejection and treatment of lupus nephritis. Pharmacokinetic drug interactions between voclosporin and a CYP3A inhibitor, inducer and substrate and a P-glycoprotein inhibitor and substrate were evaluated. METHODSVoclosporin 0.4 mg kg −1 was administered to 24 subjects in each of five studies, as follows: every 12 h (Q12H) alone and concomitantly with ketoconazole 400 mg once daily (QD); single dose before and single dose after rifampin 600 mg QD; Q12H where midazolam 7.5 mg was administered as a single dose alone before voclosporin and with last the dose of voclosporin; Q12H alone and concomitantly with verapamil 80 mg every 8 h; and Q12H with digoxin 0.25 mg QD. The noncompartmental pharmacokinetic parameters maximal concentration (Cmax) and area under the concentration-time curve (AUC) were obtained, and geometric least squares mean ratios and 90% confidence intervals were evaluated. RESULTSKetoconazole increased voclosporin Cmax (6.4-fold) and AUC (18-fold); rifampin reduced voclosporin AUC (0.9-fold); voclosporin did not change exposure of midazolam or α-hydroxy-midazolam; verapamil increased voclosporin Cmax (2.1-fold) and AUC (2.7-fold); and voclosporin increased digoxin Cmax (0.5-fold), AUC (0.25-fold) and urinary excretion (0.2-fold). CONCLUSIONSAdministration of voclosporin concomitantly with strong inhibitors and inducers of CYP3A resulted in increased and decreased exposures, respectively, and should be considered contraindicated. Drug-drug interactions involving voclosporin and CYP3A substrates are not expected. Administration of voclosporin concomitantly with inhibitors and substrates of P-glycoprotein resulted in increased voclosporin and substrate exposures, respectively. Appropriate concentration and safety monitoring is recommended with co-administration of voclosporin and P-glycoprotein substrates and inhibitors. WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT• Calcineurin inhibitors are the gold standard for immunosuppression in transplantation.• Drug-drug interactions with cytochrome P450 inducers, inhibitors and substrates and with P-glycoprotein inhibitors and substrates in these drugs with narrow therapeutic windows may impact both safety and efficacy.• Knowledge of patient and drug factors that influence drug disposition enhances the optimal dosing and successful therapy with the drug. WHAT THIS STUDY ADDS• These results provide a rationale for avoiding the co-administration of voclosporin with strong CYP3A inhibitors and CYP3A inducers.• These results suggest that co-administration of voclosporin with substrates of CYP3A would not result in increased exposure to the substrate.• These results provide a rationale for conducting appropriate concentration and safety monitoring when voclosporin is co-administered with P-glycoprotein substrates and inhibitors.

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“…While the abnormal cosmetic side effects (hypertrichosis and hirsutism) are less frequent with tacrolimus compared to cyclosporine, glucose intolerance and neurotoxicity (headache, seizures) are more common. Voclosporin, a cyclosporine analog with reduced nephrotoxicity, is a novel calcineurin inhibitor being developed for organ transplantation and currently in clinical trials: preliminary results showed a reduced risk of posttransplant diabetes compared to tacrolimus while maintaining the same efficacy in preventing rejection in kidney transplantation [4].…”

Section: Calcineurin-inhibitorsmentioning

confidence: 99%

Complications of Post-Transplant Immunosuppression

Girlanda¹

2013

Regenerative Medicine and Tissue Engineering

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The PROMISE Study: A Phase 2b Multicenter Study of Voclosporin (ISA247) Versus Tacrolimus in De Novo Kidney Transplantation

Cited by 81 publications

References 22 publications

Immunosuppressive Medications

Immunosuppressive Medications

Cytochrome P450 3A and P-glycoprotein drug-drug interactions with voclosporin

Complications of Post-Transplant Immunosuppression

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