title: The effect of single- and multiple-dose etravirine on a drug cocktail of representative cytochrome P450 probes and digoxin in healthy subjects.
abstract: 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.
authors.affiliation: Janssen Research & Development, LLC, Titusville, NJ.
authors.forename: Thomas N
authors.initials: TN
authors.lastname: Kakuda
authors.forename: Rodica M
authors.initials: RM
authors.lastname: Van Solingen-Ristea
authors.forename: Joelle
authors.initials: J
authors.lastname: Onkelinx
authors.forename: Tanja
authors.initials: T
authors.lastname: Stevens
authors.forename: Fatima
authors.initials: F
authors.lastname: Aharchi
authors.forename: Goedele
authors.initials: G
authors.lastname: De Smedt
authors.forename: Monika
authors.initials: M
authors.lastname: Peeters
authors.forename: Lorant
authors.initials: L
authors.lastname: Leopold
authors.forename: Richard M W
authors.initials: RM
authors.lastname: Hoetelmans
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism*; D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents / Q000008:administration & dosage*; D002110:Caffeine / Q000008:administration & dosage / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D003915:Dextromethorphan / Q000008:administration & dosage / Q000493:pharmacokinetics; D004077:Digoxin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D005260:Female; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics; D008875:Middle Aged; D009570:Nitriles; D009853:Omeprazole / Q000008:administration & dosage / Q000493:pharmacokinetics; D011724:Pyridazines / Q000008:administration & dosage*; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors / Q000008:administration & dosage*; D013806:Theophylline / Q000008:administration & dosage / Q000493:pharmacokinetics; D014859:Warfarin / Q000008:administration & dosage / Q000493:pharmacokinetics; D055815:Young Adult
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D019380:Anti-HIV Agents; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; D002110:Caffeine; D014859:Warfarin; D003915:Dextromethorphan; D004077:Digoxin; D003577:Cytochrome P-450 Enzyme System; D013806:Theophylline; D009853:Omeprazole; C021183:1,7-dimethylxanthine; D008874:Midazolam
keywords: HIV; P-glycoprotein; cytochrome P450; drug-drug interactions; etravirine