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Impacts of CYP2C19 genetic polymorphisms on bioavailability and effect on platelet adhesion of vicagrel, a novel thienopyridine P2Y(12) inhibitor

Authors :
Xiaoxue Zhu
Yu Xia
Yongguo Li
Xiaojuan Lai
Haijing Wei
Yifan Zhang
Xiaojiao Li
Yanhua Ding
Liu Xuefang
Hongbin Sun
Dafang Zhong
Yan Zhan
Cai Liu
Y. L. Zhu
Yanchun Gong
Liu Yongqiang
Hong Zhang
Source :
Br J Clin Pharmacol
Publication Year :
2020
Publisher :
John Wiley and Sons Inc., 2020.

Abstract

AIMS: We investigated the impacts of CYP2C19 polymorphisms on pharmacokinetics and pharmacodynamics of vicagrel in healthy Chinese subjects. METHODS: 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. RESULTS: After a loading dose, the AUC(0‐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 AUC(0‐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. CONCLUSIONS: 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.

Details

Language :
English
Database :
OpenAIRE
Journal :
Br J Clin Pharmacol
Accession number :
edsair.doi.dedup.....0a745b9c8642319757f80f372a82edbb