A pharmacokinetic study of etravirine (TMC125) co‐administered with ranitidine and omeprazole in HIV–negative volunteers

• Published in: British journal of clinical pharmacology Vol. 66; no. 4; pp. 508 - 516
• Main Authors: Schöller‐Gyüre, Monika, Kakuda, Thomas N., De Smedt, Goedele, Vanaken, Hilde, Bouche, Marie‐Paule, Peeters, Monika, Woodfall, Brian, Hoetelmans, Richard M. W.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.10.2008; Blackwell Science Inc
• Subjects: Adolescent; Adult; Anti-HIV Agents; Anti-Ulcer Agents - administration & dosage; Anti-Ulcer Agents - pharmacokinetics; Drug Administration Schedule; Drug Combinations; Drug Interactions; Drug–drug interaction; Epidemiologic Methods; etravirine; Female; Human immunodeficiency virus; Humans; Male; Middle Aged; Nitriles; non‐nucleoside reverse transcriptase inhibitor; omeprazole; Omeprazole - administration & dosage; Omeprazole - pharmacokinetics; Proton Pump Inhibitors - administration & dosage; Proton Pump Inhibitors - pharmacokinetics; Pyridazines - administration & dosage; Pyridazines - pharmacokinetics; Pyrimidines; ranitidine; Ranitidine - administration & dosage; Ranitidine - pharmacokinetics; Reverse Transcriptase Inhibitors - administration & dosage; Reverse Transcriptase Inhibitors - pharmacokinetics; TMC125; Treatment Outcome
• ISSN: 0306-5251; 1365-2125; 1365-2125
• DOI: 10.1111/j.1365-2125.2008.03214.x

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Drug–drug interactions with acid‐suppressing agents were previously described with several other antiretroviral drugs. • Etravirine (TMC125) is a next‐generation non‐nucleoside reverse transcriptase inhibitor, metabolized by CYP3A and CYP2C enzymes with demonstrated efficacy in treatment‐experienced HIV‐infected patients. • The effect of acid‐suppressing agents on the pharmacokinetics of etravirine was unknown. WHAT THIS STUDY ADDS • No clinically relevant effect was shown on the pharmacokinetics of etravirine when co‐administered with ranitidine or omeprazole, drugs that increase gastric pH. • A drug–drug interaction due to CYP2C19 inhibition by omeprazole has been identified. • Etravirine can be co‐administered with proton pump inhibitors and H2 antagonists without dose adjustments. Aims Etravirine is a next‐generation non‐nucleoside reverse transcriptase inhibitor (NNRTI) with activity against wild‐type and NNRTI‐resistant HIV. Proton pump inhibitors and H2‐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 AUClast and Cmax 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 H2 antagonists without dose adjustments.