title: Evaluation of the drug interaction potential of aplaviroc, a novel human immunodeficiency virus entry inhibitor, using a modified cooperstown 5 + 1 cocktail.
abstract: Aplaviroc is a novel CCR5 antagonist, a class of compounds under investigation as viral entry inhibitors for the treatment of human immunodeficiency virus infection. A modified Cooperstown 5+1 cocktail was used to assess the drug interaction potential of aplaviroc. Fifteen healthy subjects were administered single oral doses of caffeine (CYP1A2), warfarin (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), and midazolam (CYP3A) alone (reference treatment) and during steady-state administration of aplaviroc (400 mg every 12 hours, test treatment). Metabolite-to-parent area under the plasma concentration versus time curve (AUC) ratios (paraxanthine/caffeine and 5-hydroxyomeprazole/omeprazole), oral clearance (S-warfarin), AUC (midazolam), and metabolite-to-parent urinary excretion ratio (dextrorphan/dextromethorphan) were determined. The test-to-reference treatment ratios (geometric mean ratio and 90% confidence interval) were caffeine, 1.06 (0.97-1.17); S-warfarin, 0.93 (0.76-1.15); omeprazole, 1.07 (0.98-1.16); dextromethorphan, 1.17 (0.97-1.42); midazolam, 1.30 (1.04-1.63). No significant inhibition of CYP1A2, CYP2C9, CYP2C19, or CYP2D6 enzyme activity was observed. Mild inhibition of CYP3A isozymes should not preclude the use of concomitant CYP3A substrates in future clinical studies with aplaviroc.
authors.affiliation: GlaxoSmithKline, Research Triangle Park, NC 27709, USA. stephen.c.piscitelli@gsk.com
authors.forename: Brendan M
authors.initials: BM
authors.lastname: Johnson
authors.forename: Ivy H
authors.initials: IH
authors.lastname: Song
authors.forename: Kimberly K
authors.initials: KK
authors.lastname: Adkison
authors.forename: Julie
authors.initials: J
authors.lastname: Borland
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.forename: Yu
authors.initials: Y
authors.lastname: Lou
authors.forename: M Michelle
authors.initials: MM
authors.lastname: Berrey
authors.forename: Anne N
authors.initials: AN
authors.lastname: Nafziger
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Piscitelli
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Bertino
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D001565:Benzoates / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D065100:CCR5 Receptor Antagonists; D002110:Caffeine / Q000097:blood / Q000493:pharmacokinetics; D003915:Dextromethorphan / Q000493:pharmacokinetics / Q000652:urine; D054659:Diketopiperazines; D004347:Drug Interactions; D005260:Female; D006801:Humans; D008297:Male; D008874:Midazolam / Q000097:blood / Q000493:pharmacokinetics; D008875:Middle Aged; D009853:Omeprazole / Q000097:blood / Q000493:pharmacokinetics; D010879:Piperazines / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D013141:Spiro Compounds / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D014859:Warfarin / Q000097:blood / Q000493:pharmacokinetics
chemical_list: D019380:Anti-HIV Agents; D001565:Benzoates; D065100:CCR5 Receptor Antagonists; D054659:Diketopiperazines; D010879:Piperazines; D013141:Spiro Compounds; D002110:Caffeine; D014859:Warfarin; D003915:Dextromethorphan; C499671:aplaviroc; D001189:Aryl Hydrocarbon Hydroxylases; D009853:Omeprazole; D008874:Midazolam