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HIV/AIDS

Etravirine Has No Effect on QT and Corrected QT Interval in HIV-Negative Volunteers

Clinical Statistician, Tibotec BVBA, Mechelen, Belgium

Katrien Janssen, MSc

Clinical Statistician, Tibotec BVBA

Thomas N Kakuda, PharmD

Director of Clinical Pharmacology, Department of Human Pharmacokinetics, Tibotec Inc., Yardley, PA

Monika Schöller-Gyüre, MD

Clinical Pharmacokineticist, Tibotec BVBA

Ruth Lachaert, MSc

Senior Manager, Global Clinical Operations, Tibotec BVBA

Richard MW Hoetelmans, PhD

Head of Pharmacology, Tibotec BVBA

Brian Woodfall, MD

Senior Director, Global Clinical Development, Tibotec BVBA

Goedele De Smedt, MD

Director, Global Clinical Development, Etravirine Clinical Lead, Tibotec BVBA

Reprints: Mrs. Peeters, Tibotec BVBA, Gen De Wittelaan, L11B 3, 2800, Mechelen, Belgium, fax 32 15 444 291, mpeeter7{at}tibbe.jnj.com

BACKGROUND: Etravirine (TMC125), a next-generation nonnucleoside reverse transcriptase inhibitor, has shown antiviral efficacy in 2 large Phase 3 trials. In vitro and in vivo studies have shown that etravirine is not associated with proarrhythmic potential. Electrocardiograms (ECGs) from healthy and HIV 1–infected volunteers showed no clinically relevant changes.

OBJECTIVE: To evaluate the effect of 2 etravirine dosing regimens on QT/corrected QT interval (QTc) in HIV-negative volunteers and assess pharmacokinetic and additional safety parameters.

METHODS: A double-blind, double-dummy, randomized, placebo- and active-controlled, 4-period crossover trial was conducted in 41 HIV-negative volunteers. Participants received 4 regimens: etravirine 200 mg twice daily, etravirine 400 mg once daily, moxifloxacin 400 mg once daily (positive control), and placebo in separate 8-day sessions, with each followed by a washout period of 14 or more days. On days –1, 1, and 8 of each session, ECGs were recorded at 11 time points over 12 hours. Pharmacokinetic profiles of etravirine regimens were evaluated and safety was assessed.

RESULTS: Thirty-seven subjects completed the study. For etravirine, the upper limit of the 90% CIs of mean time-matched differences in QTc determined using Fridericia's formula (QTcF) was below 10 msec at all time points, the threshold for prolonged QT as defined by regulatory guidelines. The maximum mean (90% CI) difference of time-matched changes in QTcF versus placebo on day 1 was +0.1 msec (–2.6 to 2.9), –0.2 msec (–2.6 to 2.1), and +10.1 msec (7.3 to 12.8) for etravirine 200 mg twice daily, etravirine 400 mg once daily, and moxifloxacin, respectively. On day 8, these values were +0.6 msec (–2.1 to 3.3), –1.0 msec (–4.4 to 2.5), and +10.3 msec (6.8 to 13.9), respectively. Etravirine produced no clinically significant changes in other ECG parameters. No significant differences between males and females were observed. Both etravirine regimens had similar pharmacokinetic exposure and safety profiles.

CONCLUSIONS: Etravirine does not prolong the QTc interval. No clinically relevant ECG changes were observed in HIV-negative volunteers. Short-term dosing of etravirine in HIV-negative volunteers was generally safe and well tolerated.

Key Words: electrocardiogram, etravirine, QT interval, safety, tolerability

Published Online, April 29, 2008. www.theannals.com, DOI 10.1345/aph.1K681