Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently

Prasugrel and clopidogrel inhibit platelet aggregation through active metabolite formation. Prasugrel's active metabolite ( R-138727) is formed primarily by cytochrome P450 ( CYP) 3A and CYP2B6, with roles for CYP2C9 and CYP2C19. Clopidogrel's activation involves two sequential steps by CYP3A, CYP1A2, CYP2C9, CYP2C19, and/or CYP2B6. In a randomized crossover study, healthy subjects received a loading dose ( LD) of prasugrel ( 60 mg) or clopidogrel ( 300 mg), followed by five daily maintenance doses ( MDs) ( 15 and 75 mg, respectively) with or without the potent CYP3A inhibitor ketoconazole ( 400 mg/day). Subjects had a 2-week washout between periods. Ketoconazole decreased R-138727 and clopidogrel active metabolite C-max ( maximum plasma concentration) 34-61% after prasugrel and clopidogrel dosing. Ketoconazole did not affect R-138727 exposure or prasugrel's inhibition of platelet aggregation ( IPA). Ketoconazole decreased clopidogrel's active metabolite AUC(0-24) ( area under the concentration-time curve to 24 h postdose) 22% ( LD) to 29% ( MD) and reduced IPA 28% ( LD) to 33% ( MD). We conclude that CYP3A4 and CYP3A5 inhibition by ketoconazole affects formation of clopidogrel's but not prasugrel's active metabolite. The decreased formation of clopidogrel's active metabolite is associated with reduced IPA.