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Sotrastaurin and tacrolimus coadministration: effects on pharmacokinetics and biomarker responses.

Kovarik, John M and Stitah, Sylvie and Slade, Alan and Vitaliti, Alessandra and Straube, Frank and Grenet, Olivier and Winter, Serge and Sfikas, Nikolaos and Seiberling, Michael (2010) Sotrastaurin and tacrolimus coadministration: effects on pharmacokinetics and biomarker responses. Journal of Clinical Pharmacology, 50 (11). pp. 1260-1266. ISSN 1552-4604

Abstract

Sotrastaurin is an immunosuppressant that inhibits protein kinase C. In the prevention of acute rejection in organ transplantation, sotrastaurin might be combined with tacrolimus. A drug interaction study was performed in 18 healthy subjects who received single oral doses of sotrastaurin 400 mg, tacrolimus 7 mg, and the drug combination. Drug blood levels and lymphocyte activation and proliferation were measured. Tacrolimus did not alter the pharmacokinetics of sotrastaurin; however, sotrastaurin increased tacrolimus area under the concentration-time curve by 2.0-fold (90% confidence interval, 1.8-2.1). Production of interleukin-2 and tumor necrosis factor by T cells activated via calcium-independent pathways was inhibited by 75% ± 22% from baseline by sotrastaurin. Interleukin-2 messenger RNA levels were decreased by 90% ± 9% from baseline by sotrastaurin. Addition of tacrolimus to sotrastaurin had minimal or no effect on these biomarkers, consistent with tacrolimus’ mechanism of action. Lymphocyte proliferation induced via calcium-dependent pathways was decreased from baseline by 82% ± 9% by sotrastaurin, 76% ± 11% by tacrolimus, and 96% ± 2% for the drug combination. How sotrastaurin and tacrolimus could be partnered in an immunosuppressive regimen will need to be established in the context of controlled clinical trials in organ transplant patients, taking into account the pharmacokinetic interaction on tacrolimus and the potentially enhanced immunosuppressive activity of this drug combination.

Item Type: Article
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Additional Information: author can archive post-print (ie final draft post-refereeing); Publisher's version/PDF cannot be used
Keywords: Immunomodulators; sotrastaurin; tacrolimus; drug interactions; protein kinase C
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Date Deposited: 13 Oct 2015 13:15
Last Modified: 13 Oct 2015 13:15
URI: https://oak.novartis.com/id/eprint/4362

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