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

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, USACorrespondence: Simon ZhouTranslational De...

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Autores principales:	Li Y, Palmisano M, Sun D, Zhou S
Formato:	article
Lenguaje:	EN
Publicado:	Dove Medical Press 2020
Materias:	pharmacokinetic disposition cyclosporine and voclosporin Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/2d8644db28da449d8f59566a08ebf544
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spelling	oai:doaj.org-article:2d8644db28da449d8f59566a08ebf5442021-12-02T10:21:01ZPharmacokinetic Disposition Difference Between Cyclosporine and Voclosporin Drives Their Distinct Efficacy and Safety Profiles in Clinical Studies1179-1438https://doaj.org/article/2d8644db28da449d8f59566a08ebf5442020-07-01T00:00:00Zhttps://www.dovepress.com/pharmacokinetic-disposition-difference-between-cyclosporine-and-voclos-peer-reviewed-article-CPAAhttps://doaj.org/toc/1179-1438Yan 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, USACorrespondence: Simon ZhouTranslational Development and Clinical Pharmacology, Celgene Corporation, 556 Morris Avenue, Summit, NJ 07920, USATel +1 908-673-9284Fax +1 908-673-2842Email szhou@celgene.comBackground: 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 voclosporinLi YPalmisano MSun DZhou SDove Medical Pressarticlepharmacokineticdispositioncyclosporine and voclosporinTherapeutics. PharmacologyRM1-950ENClinical Pharmacology: Advances and Applications, Vol Volume 12, Pp 83-96 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	pharmacokinetic disposition cyclosporine and voclosporin Therapeutics. Pharmacology RM1-950
spellingShingle	pharmacokinetic disposition cyclosporine and voclosporin Therapeutics. Pharmacology RM1-950 Li Y Palmisano M Sun D Zhou S Pharmacokinetic Disposition Difference Between Cyclosporine and Voclosporin Drives Their Distinct Efficacy and Safety Profiles in Clinical Studies
description	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, USACorrespondence: Simon ZhouTranslational Development and Clinical Pharmacology, Celgene Corporation, 556 Morris Avenue, Summit, NJ 07920, USATel +1 908-673-9284Fax +1 908-673-2842Email szhou@celgene.comBackground: 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
format	article
author	Li Y Palmisano M Sun D Zhou S
author_facet	Li Y Palmisano M Sun D Zhou S
author_sort	Li Y
title	Pharmacokinetic Disposition Difference Between Cyclosporine and Voclosporin Drives Their Distinct Efficacy and Safety Profiles in Clinical Studies
title_short	Pharmacokinetic Disposition Difference Between Cyclosporine and Voclosporin Drives Their Distinct Efficacy and Safety Profiles in Clinical Studies
title_full	Pharmacokinetic Disposition Difference Between Cyclosporine and Voclosporin Drives Their Distinct Efficacy and Safety Profiles in Clinical Studies
title_fullStr	Pharmacokinetic Disposition Difference Between Cyclosporine and Voclosporin Drives Their Distinct Efficacy and Safety Profiles in Clinical Studies
title_full_unstemmed	Pharmacokinetic Disposition Difference Between Cyclosporine and Voclosporin Drives Their Distinct Efficacy and Safety Profiles in Clinical Studies
title_sort	pharmacokinetic disposition difference between cyclosporine and voclosporin drives their distinct efficacy and safety profiles in clinical studies
publisher	Dove Medical Press
publishDate	2020
url	https://doaj.org/article/2d8644db28da449d8f59566a08ebf544
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Pharmacokinetic Disposition Difference Between Cyclosporine and Voclosporin Drives Their Distinct Efficacy and Safety Profiles in Clinical Studies

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