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

Abstract

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. AimsEtravirine 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. MethodsIn 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. ResultsNineteen 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. ConclusionsRanitidine 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.

Biotransformation of the Antiretroviral Drug Etravirine: Metabolite Identification, Reaction Phenotyping, and Characterization of Autoinduction of Cytochrome P450-Dependent Metabolism

“…The investigators in that study found that coadministration of ETR with omeprazole, which inhibits CYP2C19 activity, resulted in 41% greater ETR exposure in HIV-negative adults (Schöller-Gyüre et al, 2008). Therefore, our findings that ETR increases the mRNA expression of CYP3A4 and that CYP2C19 is principally responsible for the formation of the primary monohydroxy and dihydroxy metabolites of ETR provide a mechanistic basis for understanding these interactions.…”

The Dual Role of Pharmacogenetics in HIV Treatment: Mutations and Polymorphisms Regulating Antiretroviral Drug Resistance and Disposition

“…Etravirine metabolism is known to be dependent upon several P450 isoenzymes, such as CYP2C19, CYP2C9, and CYP3A4 (Seminari et al, 2008). Concomitant administration of etravirine and omeprazole, a CYP2C19 substrate, caused a 41% increase in the area under etravirine's plasma concentration curve in subjects who were not seropositive for HIV (Schöller-Gyü re et al, 2008). This drug-drug interaction can be explained by competitive inhibition of CYP2C19 by omeprazole, which leads to a decrease in etravirine metabolism by this isoenzyme.…”

Minimal Pharmacokinetic Interaction between the Human Immunodeficiency Virus Nonnucleoside Reverse Transcriptase Inhibitor Etravirine and the Integrase Inhibitor Raltegravir in Healthy Subjects

“…The analytical method for the determination of raltegravir concentrations in human plasma involved isolation, via 96-well liquid-liquid extraction, of the analyte and internal standard from plasma, followed by reverse-phase highpressure liquid chromatography-tandem mass spectrometry analysis as previously described (11), while plasma concentrations of etravirine were determined by a validated liquid chromatography-tandem mass spectrometry method without extraction (13). For each analyte, no cross-interference was observed in the respective assays.…”