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

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. I...

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Bibliographic Details
Published in:Journal of clinical pharmacology 2008-03, Vol.48 (3), p.322-329
Main Authors: Schöller-Gyüre, Monika, van den Brink, Wim, Kakuda, Thomas N., Woodfall, Brian, Smedt, Goedel D., Vanaken, Hilde, Stevens, Tanja, Peeters, Monika, Vandermeulen, Kati, Hoetelmans, Richard M. W.
Format: Article
Language:English
Subjects:
Adult
Area Under Curve
Dose-Response Relationship, Drug
Drug Interactions
Drug Therapy, Combination
drug-drug interaction
etravirine
Exanthema - chemically induced
Headache - chemically induced
HIV Seronegativity
Human immunodeficiency virus 1
Humans
Male
Metabolic Clearance Rate - drug effects
methadone
Methadone - adverse effects
Methadone - chemistry
Methadone - pharmacokinetics
Middle Aged
Nausea - chemically induced
nonnucleoside reverse transcriptase inhibitor
Pyridazines - pharmacology
Reverse Transcriptase Inhibitors - pharmacology
Stereoisomerism
Tablets
TMC125
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Summary: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.
ISSN:0091-2700
1552-4604
DOI:10.1177/0091270007310387