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0091270007310387v1
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DRUG INTERACTIONS

Pharmacokinetic and Pharmacodynamic Study of the Concomitant Administration of Methadone and TMC125 in HIV-Negative Volunteers

Monika Schöller-Gyüre, MD, Wim van den Brink, MD, PhD, Thomas N. Kakuda, PharmD, Brian Woodfall, MD, Goedele De Smedt, MD, Hilde Vanaken, PhD, Tanja Stevens, RN, Monika Peeters, MSc, Kati Vandermeulen, BSc and Richard M. W. Hoetelmans, PhD

From Tibotec BVBA, Mechelen, Belgium (Dr Schöller-Gyüre, Dr Woodfall, Dr De Smedt, Dr Vanaken, Ms Stevens, Ms Peeters, Ms Vandermeulen, Dr Hoetelmans); Department of Psychiatry, Academic Medical Center, University of Amsterdam, The Netherlands (Dr van den Brink); and Tibotec, Inc, Yardley, Pennsylvania (Dr Kakuda).

TMC125 is a nonnucleoside reverse transcriptase inhibitor (NNRTI) with potent in vitro activity against wild-type and NNRTI-resistant HIV-1. TMC125 is an inducer of CYP3A and an inhibitor of CYP2C. This trial evaluated the effect of TMC125 on the pharmacokinetics and pharmacodynamics of methadone. In an open-label, add-on, 1-way interaction trial, 16 male HIV-negative volunteers on stable methadone maintenance therapy received 100 mg TMC125 bid for 14 days. Plasma concentrations and pharmacokinetic parameters of R- and S-methadone isomers were determined on days -1, 7, and 14 and of TMC125 on days 7 and 14. Safety and tolerability were assessed. The LSmeans ratios (90% confidence interval) for AUC24h, Cmax, and Cmin of the pharmacologically active R-methadone were 1.08 (1.02-1.13), 1.03 (0.97-1.09), and 1.12 (1.05-1.19), respectively, on day 7 and 1.06 (0.99-1.13), 1.02 (0.96-1.09), and 1.10 (1.02-1.19), respectively, on day 14 compared with methadone alone. No withdrawal symptoms were observed; dose adjustment of methadone was not required. The concomitant administration of TMC125 and methadone was generally safe and well tolerated. TMC125 has no clinically relevant effect on the pharmacokinetics or pharmacodynamics of methadone. No dose adjustment for methadone is anticipated when coadministered with TMC125.

Key Words: TMC125 • etravirine • methadone • nonnucleoside reverse transcriptase inhibitor • drug-drug interaction

Address for correspondence: Monika Schöller-Gyüre, MD, Tibotec BVBA, Generaal De Wittelaan L11B 3, B-2800 Mechelen, Belgium; e-mail: mscholle{at}tibbe.jnj.com.


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