A pharmacokinetic study of etravirine (TMC125) co-administered with ranitidine and omeprazole in HIV-negative volunteers.
OBJECTIVE
Etravirine is a next-generation non-nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild-type and NNRTI-resistant HIV. Proton pump inhibitors and H(2)-antagonists are frequently used in the HIV-negative-infected population, and drug-drug interactions have been described with other antiretrovirals. This study evaluated the effect of steady-state omeprazole and ranitidine on the pharmacokinetics of a single dose of etravirine.


METHODS
In an open-label, randomized, one-way, three-period crossover trial, HIV-negative volunteers randomly received a single dose of 100 mg etravirine alone (treatment A); 11 days of 150 mg ranitidine b.i.d. (treatment B); and 11 days of 40 mg omeprazole q.d. (treatment C). A single dose of 100 mg etravirine was co-administered on day 8 of sessions 2 and 3. Each session was separated by a 14-day wash-out.


RESULTS
Nineteen volunteers (seven female) participated. When a single dose of etravirine was administered in the presence of steady-state ranitidine, etravirine least squares means ratios (90% confidence interval) for AUC(last) and C(max) were 0.86 (0.76, 0.97) and 0.94 (0.75, 1.17), respectively, compared with administration of etravirine alone. When administered with steady-state omeprazole, these values were 1.41 (1.22, 1.62) and 1.17 (0.96, 1.43), respectively. Co-administration of a single dose of etravirine and ranitidine or omeprazole was generally safe and well tolerated.


CONCLUSIONS
Ranitidine slightly decreased etravirine exposure, whereas omeprazole increased it by approximately 41%. The increased exposure of etravirine when co-administered with omeprazole is attributed to CYP2C19 inhibition. Considering the favourable safety profile of etravirine, these changes are not clinically relevant. Etravirine can be co-administered with proton pump inhibitors and H(2) antagonists without dose adjustments.
Schöller-Gyüre
Monika
M
Tibotec BVBA, Mechelen, Belgium. mscholle@tibbe.jnj.com
Kakuda
Thomas N
TN
De Smedt
Goedele
G
Vanaken
Hilde
H
Bouche
Marie-Paule
MP
Peeters
Monika
M
Woodfall
Brian
B
Hoetelmans
Richard M W
RM
D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents; D000897:Anti-Ulcer Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004334:Drug Administration Schedule; D004338:Drug Combinations; D004347:Drug Interactions; D004812:Epidemiologic Methods; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009570:Nitriles; D009853:Omeprazole / Q000008:administration & dosage / Q000493:pharmacokinetics*; D054328:Proton Pump Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011724:Pyridazines / Q000008:administration & dosage / Q000493:pharmacokinetics*; D011743:Pyrimidines; D011899:Ranitidine / Q000008:administration & dosage / Q000493:pharmacokinetics*; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage / Q000493:pharmacokinetics*; D016896:Treatment Outcome
D019380:Anti-HIV Agents; D000897:Anti-Ulcer Agents; D004338:Drug Combinations; D009570:Nitriles; D054328:Proton Pump Inhibitors; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; D011899:Ranitidine; D009853:Omeprazole