J Clin Pharmacol
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DRUG INTERACTIONS

Evaluation of the Drug Interaction Potential of Aplaviroc, a Novel Human Immunodeficiency Virus Entry Inhibitor, Using a Modified Cooperstown 5 + 1 Cocktail

Brendan M. Johnson, PhD, Ivy H. Song, PhD, Kimberly K. Adkison, PhD, Julie Borland, BPharm, Lei Fang, MS, Yu Lou, MS, M. Michelle Berrey, MD, Anne N. Nafziger, MD, MHS, Stephen C. Piscitelli, PharmD and Joseph S. Bertino, Jr, PharmD, FCP

From GlaxoSmithKline, Research Triangle Park, North Carolina (Dr Johnson, Dr Song, Dr Adkison, Ms Borland, Mr Fang, Ms Lou, Dr Berrey, Dr Piscitelli) and Bassett Healthcare, Cooperstown, New York (Dr Nafziger, Dr Bertino). Joseph S. Bertino, Jr, is a fellow of the American College of Clinical Pharmacology.

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.

Key Words: Cytochrome P450 • biomarker • CCR5 • drug interactions

Address for reprints: Stephen C. Piscitelli, PharmD, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709; e-mail: stephen.c.piscitelli{at}gsk.com.


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