Pharmacokinetics of elvitegravir and etravirine following coadministration of ritonavir-boosted elvitegravir and etravirine.
BACKGROUND
This crossover, open-label clinical study evaluated the potential for clinically relevant drug interactions between ritonavir-boosted elvitegravir (elvitegravir/r), an HIV integrase inhibitor, and etravirine, a non-nucleoside reverse transcriptase inhibitor.


METHODS
Healthy volunteers were randomized into one of two groups, each with two arms. Group 1 (n = 20) followed a sequence of 10-day dosing of elvitegravir/r (150/100 mg once daily) and elvitegravir/r plus etravirine (200 mg twice daily) or the reverse (n = 10 per sequence). Group 2 (n = 14) followed a sequence of 10-day dosing of etravirine and etravirine plus elvitegravir/r or the reverse (n = 7 per sequence), all under fed conditions. Elvitegravir, ritonavir and etravirine pharmacokinetics were determined on days 10 and 20 using non-compartmental analyses. Lack of pharmacokinetic alteration bounds for 90% confidence intervals (CI) about the geometric mean ratio (GMR; coadministration versus alone) were 70-143% for elvitegravir and ritonavir pharmacokinetics (maximum concentration [C(max)], concentration at the end of the dosing interval [C(tau)] and area under the plasma concentration-time curve [AUC(tau); 0-24 h] and 80-125% for etravirine pharmacokinetics (AUC(tau) 0-12 h).


RESULTS
Of the 34 enrolled participants, 31 completed the study. There were three discontinuations, but none were caused by adverse events (AEs). The most common treatment-emergent AE was headache. Elvitegravir pharmacokinetic GMR was 6-7% higher following elvitegravir/r plus etravirine dosing versus elvitegravir/r. The GMR for etravirine and ritonavir AUC(tau) were 2.4% and 12.3% lower, respectively. Importantly, the 90% CI for elvitegravir and etravirine pharmacokinetics and AUC(tau) and C(max) for ritonavir were within the lack of alteration bounds.


CONCLUSIONS
Elvitegravir/r and etravirine do not undergo clinically relevant drug interactions and can be coadministered without dose adjustment.
Ramanathan
Srinivasan
S
Gilead Sciences, Inc., Foster City, CA, USA. sramanathan@gilead.com
Kakuda
Thomas N
TN
Mack
Rebecca
R
West
Steve
S
Kearney
Brian P
BP
D000293:Adolescent; D000328:Adult; D018592:Cross-Over Studies; D004359:Drug Therapy, Combination; D005260:Female; D017320:HIV Protease Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D011724:Pyridazines / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D011743:Pyrimidines; D015363:Quinolones / Q000008:administration & dosage / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D019438:Ritonavir / Q000008:administration & dosage* / Q000009:adverse effects
D017320:HIV Protease Inhibitors; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D015363:Quinolones; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; C509700:elvitegravir; D019438:Ritonavir