The effect of single- and multiple-dose etravirine on a drug cocktail of representative cytochrome P450 probes and digoxin in healthy subjects

• Published in: Journal of clinical pharmacology Vol. 54; no. 4; pp. 422 - 431
• Main Authors: Kakuda, Thomas N., Van Solingen-Ristea, Rodica M., Onkelinx, Joelle, Stevens, Tanja, Aharchi, Fatima, De Smedt, Goedele, Peeters, Monika, Leopold, Lorant, Hoetelmans, Richard M.W.
• Format: Journal Article
• Language: English
• Published: England Blackwell Publishing Ltd 01-04-2014; American College of Clinical Pharmacology; Wiley Subscription Services, Inc
• Subjects: Adolescent; Adult; Anti-HIV Agents - administration & dosage; ATP-Binding Cassette, Sub-Family B, Member 1 - metabolism; Caffeine - administration & dosage; Caffeine - pharmacokinetics; Cross-Over Studies; Cytochrome; Cytochrome P-450 Enzyme System - metabolism; cytochrome P450; Dextromethorphan - administration & dosage; Dextromethorphan - pharmacokinetics; Digoxin - administration & dosage; Digoxin - pharmacokinetics; drug-drug interactions; etravirine; Female; Healthy Volunteers; HIV; Humans; Male; Midazolam - administration & dosage; Midazolam - pharmacokinetics; Middle Aged; Omeprazole - administration & dosage; Omeprazole - pharmacokinetics; P-glycoprotein; Pyridazines - administration & dosage; Reverse Transcriptase Inhibitors - administration & dosage; Theophylline - administration & dosage; Theophylline - pharmacokinetics; Warfarin - administration & dosage; Warfarin - pharmacokinetics; Young Adult; P-glycoprotein; etravirine; drug-drug interactions; cytochrome P450; HIV
• ISSN: 0091-2700; 1552-4604
• DOI: 10.1002/jcph.214

The effect of etravirine on cytochrome P450 (CYP) enzymes and P‐glycoprotein were evaluated in two randomized, crossover trials in healthy subjects. A modified Cooperstown 5 + 1 cocktail was utilized to determine the effects of etravirine on single‐dose pharmacokinetics of model CYP probes. The cocktail was administered alone, then, after a 14‐day washout, etravirine 200 mg twice daily (bid) was given for 14 days with cocktail on days 1 and 14. In a separate study, digoxin (0.5 mg) was administered alone, then, after a 14‐day washout, etravirine 200 mg bid was administered for 12 days with digoxin on day 8. In the cocktail study, the AUClast least squares mean (LSM) ratios (90% confidence intervals [CIs]) for cocktail + etravirine versus cocktail were 0.93 (0.88, 0.99; paraxanthine), 0.58 (0.44, 0.75; 7‐OH‐S‐warfarin), 0.43 (0.20, 0.96; 5‐OH‐omeprazole), 0.85 (0.78, 0.94; dextrorphan), and 0.69 (0.64, 0.74; midazolam). Digoxin AUC0–8h was slightly increased with etravirine coadministration (LSM ratio 1.18 [0.90, 1.56]). These data suggest that etravirine is a weak CYP3A isozyme inducer and minimally inhibits CYP2C9, 2C19, and P‐glycoprotein activity.