alexa An Evaluation of the Potential of Cytochrome P450 3A4-Mediated Drug- Drug Interactions with Desvenlafaxine Use | OMICS International | Abstract
ISSN: 0975-0851

Journal of Bioequivalence & Bioavailability
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Research Article

An Evaluation of the Potential of Cytochrome P450 3A4-Mediated Drug- Drug Interactions with Desvenlafaxine Use

Alice Nichols1*, Yali Liang1, Kyle Matschke1, Jeff Paul2, Jessica Behrle2, Joel Posener2, Alain Patat2, Shannon Lubaczewski1, Gabriel Braley1 and Tanya Ramey3

1Clinical Pharmacology, Primary Care, Pfizer Inc., 500 Arcola Drive, Collegeville, PA 19426, USA

2Formerly of Pfizer Inc, Collegeville, PA, USA

3Pfizer Inc, Groton, CT, USA

*Corresponding Author:
Alice Nichols
Senior Director, Clinical Pharmacology
Primary Care, Pfizer Inc.
500 Arcola Drive, Collegeville
PA 19426, USA
Tel: 484-865-8741
Fax: 484-865-9075
E-mail: [email protected]

Received Date: December 20, 2012; Accepted Date: January 21, 2013; Published Date: January 27, 2013

Citation: Nichols A, Liang Y, Matschke K, Paul J, Behrle J, et al. (2013) An Evaluation of the Potential of Cytochrome P450 3A4-Mediated Drug-Drug Interactions with Desvenlafaxine Use. J Bioequiv Availab 5: 053-059. doi: 10.4172/jbb.1000134

Copyright: © 2013 Nichols A, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

A series of 3 open-label, 2-period, sequential studies were conducted to assess the impact of desvenlafaxine cytochrome P450 3A4 (CYP3A4) enzyme-mediated metabolism, and the effect of CYP3A4 inhibition on desvenlafaxine metabolism. Study 1 evaluated a single dose of desvenlafaxine 400 mg administered alone or with a CYP3A4 inhibitor (ketoconazole [400 mg/d for 8 days]). Studies 2 and 3 evaluated a single dose of CYP3A4 substrate (midazolam [4 mg]) administered alone or with multiple doses of desvenlafaxine 400 mg and 50 mg (the recommended therapeutic dose), respectively, to assess the potential inhibitory effect of desvenlafaxine. In study 1, desvenlafaxine peak plasma concentration (Cmax) and area under the plasma concentration-versus-time curve (AUC) geometric least-squares mean ratios (desvenlafaxine and ketoconazole vs. desvenlafaxine alone) were 108% (90% confidence interval [CI], 100% to 117%) and 143% (90% CI, 138% to 149%), respectively. Total oral clearance decreased by 29% with ketoconazole coadministration. In studies 2 and 3, Cmax and AUC geometric least-squares mean ratios (midazolam and desvenlafaxine vs. midazolam alone) were 84% (90% CI, 72% to 97%) and 69% (90% CI, 61% to 78%), respectively, for the desvenlafaxine 400-mg dose, and 86% (90% CI, 79% to 94%) and 71% (90% CI, 65% to 78%), respectively, for the desvenlafaxine 50-mg dose. No serious adverse events or safety-related discontinuations occurred. Desvenlafaxine is minimally metabolized by CYP3A4 and does not appear to inhibit CYP3A4.

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