Safety, tolerability, and preliminary efficacy of 48 weeks of etravirine therapy in a phase IIb dose-ranging study involving treatment-experienced patients with HIV-1 infection

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

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. 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 AUC(24h), C(max), and C(min) 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 TMC12

Pharmacokinetic Interactions of Maraviroc with Darunavir-Ritonavir, Etravirine, and Etravirine-Darunavir-Ritonavir in Healthy Volunteers: Results of Two Drug Interaction Trials▿†

The effects of darunavir-ritonavir at 600 and 100 mg twice daily (b.i.d.) alone, 200 mg of etravirine b.i.d. alone, or 600 and 100 mg of darunavir-ritonavir b.i.d. with 200 mg etravirine b.i.d. at steady state on the steady-state pharmacokinetics of maraviroc, and vice versa, in healthy volunteers were investigated in two phase I, randomized, two-period crossover studies. Safety and tolerability were also assessed. Coadministration of 150 mg maraviroc b.i.d. with darunavir-ritonavir increased the area under the plasma concentration-time curve from 0 to 12 h (AUC12) for maraviroc 4.05-fold relative to 150 mg of maraviroc b.i.d. alone. Coadministration of 300 mg maraviroc b.i.d. with etravirine decreased the maraviroc AUC12 by 53% relative to 300 mg maraviroc b.i.d. alone. Coadministration of 150 mg maraviroc b.i.d. with etravirine-darunavir-ritonavir increased the maraviroc AUC12 3.10-fold relative to 150 mg maraviroc b.i.d. alone. Maraviroc did not significantly affect the pharmacokinetics of etravirine, darunavir, or ritonavir. Short-term coadministration of maraviroc with darunavir-ritonavir, etravirine, or both was generally well tolerated, with no safety issues reported in either trial. Maraviroc can be coadministered with darunavir-ritonavir, etravirine, or etravirine-darunavir-ritonavir. Maraviroc should be dosed at 600 mg b.i.d. with etravirine in the absence of a potent inhibitor of cytochrome P450 3A (CYP3A) (i.e., a boosted protease inhibitor) or at 150 mg b.i.d. when coadministered with darunavir-ritonavir with or without etravirine