Etravirine has no effect on QT and corrected QT interval in HIV-negative volunteers.
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.
Peeters
Monika
M
Tibotec BVBA, Mechelen, Belgium. mpeeter7@tibbe.jnj.com
Janssen
Katrien
K
Kakuda
Thomas N
TN
Schöller-Gyüre
Monika
M
Lachaert
Ruth
R
Hoetelmans
Richard M W
RM
Woodfall
Brian
B
De Smedt
Goedele
G
D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D000890:Anti-Infective Agents / Q000009:adverse effects; D001372:Aza Compounds / Q000009:adverse effects; D016001:Confidence Intervals; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077266:Moxifloxacin; D009570:Nitriles; D011724:Pyridazines / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D011743:Pyrimidines; D011804:Quinolines / Q000009:adverse effects; D012737:Sex Factors
D019380:Anti-HIV Agents; D000890:Anti-Infective Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D011804:Quinolines; C451734:etravirine; D000077266:Moxifloxacin