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Pharmacokinetic Disposition Difference Between Cyclosporine and Voclosporin Drives Their Distinct Efficacy and Safety Profiles in Clinical Studies

Authors Li Y, Palmisano M, Sun D, Zhou S

Received 27 March 2020

Accepted for publication 10 June 2020

Published 1 July 2020 Volume 2020:12 Pages 83—96

DOI https://doi.org/10.2147/CPAA.S255789

Checked for plagiarism Yes

Review by Single anonymous peer review

Peer reviewer comments 3

Editor who approved publication: Professor Arthur Frankel


Yan Li,1 Maria Palmisano,1 Duxin Sun,2 Simon Zhou1

1Translational Development and Clinical Pharmacology, Celgene Corporation, Summit, NJ 07920, USA; 2Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA

Correspondence: Simon Zhou
Translational Development and Clinical Pharmacology, Celgene Corporation, 556 Morris Avenue, Summit, NJ 07920, USA
Tel +1 908-673-9284
Fax +1 908-673-2842
Email szhou@celgene.com

Background: Voclosporin, a more potent derivative of cyclosporine, has been studied extensively in patients with immunologic disorders such as psoriasis, organ transplantation, uvetitis and lupus nephritis. Although better tolerated and safer than cyclosporine, voclosporin is inferior to cyclosporine in treating psoriasis, non-inferior to tacrolimus in organ transplantation and efficacious in treating lupus nephritis.
Methods: The pharmacokinetic dispositions of voclosporin and cyclosporine in central and peripheral compartments were analyzed and correlated with their distinct clinical efficacy and safety profiles.
Results: Both drugs demonstrated non-linear pharmacokinetics with increasing doses, more prominently at lower doses of voclosporin than at 10-fold higher doses of cyclosporine. Repeated lower dosing of voclosporin produced preferential calcineurin inhibition in and near blood circulation, leading to relatively lower cardiovascular and renal adverse effects but inferior efficacy for psoriasis compared to cyclosporine. With 10-fold higher plasma levels and deeper tissue penetration, cyclosporine has more prevalent renal and cardiac toxicities but superior efficacy to treat psoriasis.
Conclusion: Although the two drugs are similar in structure and mechanism of action, the high potency and low dose compounded by the non-linear disposition of voclosporin resulted in more systemic versus local calcineurin inhibition than with cyclosporine. The dispositional difference between voclosporin and cyclosporine accounted for the puzzling efficacy and safety observations in different patients and was the basis for their optimal and differential use in treating diverse immunologic disorders.

Keywords: pharmacokinetic, disposition, cyclosporine and voclosporin

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