Impacts of CYP2C19 genetic polymorphisms on bioavailability and effect on platelet adhesion of vicagrel, a novel thienopyridine P2Y12 inhibitor.

Abstract

We investigated the impacts of CYP2C19 polymorphisms on pharmacokinetics and pharmacodynamics of vicagrel in healthy Chinese subjects. CYP2C19 extensive metabolizers (EMs), intermediate metabolizers (IMs) and poor metabolizers (PMs; 16 subjects/group) participated in a randomized, open-label, 2-period cross-over study. Each study period lasted 7 days, with a loading dose of 24 mg of vicagrel or 300 mg of clopidogrel on day 1, and maintenance doses of 6 mg of vicagrel or 75 mg of clopidogrel daily from day 2 to day 7. The pharmacokinetics and pharmacodynamics were assessed on day 1 and day 7. After a loading dose, the AUC0-t of the active metabolite H4 by vicagrel was slightly lower in IMs and PMs (decreased by 21 and 27%, respectively) compared to EMs. Similar results were found after maintenance doses. In EMs, the AUC0-t of H4 by vicagrel was somewhat higher than clopidogrel after the loading dose, and comparable with clopidogrel (90% confidence interval 0.94, 1.21) after the maintenance doses. However, it was much higher than clopidogrel in PMs, with a 1.28-fold (loading dose) and a 73% (maintenance doses) increases compared to clopidogrel (P < 0.001). Consequently, the inhibition of platelet aggregation by vicagrel was greater than clopidogrel after both loading dose (28.2 vs 12.4% at 4 hours, P < 0.01) and maintenance doses (42.8 vs 24.6% at 4 hours, P < 0.001) in PMs. CYP2C19 polymorphisms have less impact on vicagrel as compared to clopidogrel. Drug exposure and response to vicagrel in PMs were even higher than to clopidogrel in IMs.