Effect of CYP3A4∗1G and CYP3A5∗3 Polymorphisms on Pharmacokinetics and Pharmacodynamics of Ticagrelor in Healthy Chinese Subjects

Abstract

Ticagrelor is the first reversible, direct-acting, potent P2Y₁₂ receptor antagonist in management of acute coronary syndromes. It is rapidly absorbed and extensively metabolized. AR-C124910XX, the major active metabolite, antagonizes the P2Y₁₂ receptor at approximately equal potency. The metabolism of ticagrelor to AR-C124910XX involves CYP3A4 and CYP3A5. <i>CYP3A</i> polymorphisms have been well documented, and <i>CYP3A4^∗1G</i> (g.20230G>A, rs2242480) and <i>CYP3A5^∗3</i> (g.6986A>G, rs776746) are the most important single nucleotide polymorphisms in Chinese. Genetic differences in CYP3A4 and CYP3A5 expression in human volunteers and patients might affect the clearance of ticagrelor or AR-C124910XX <i>in vivo</i> resulting in subsequent variable patient response. Thus, this study is designed to explore the effects of <i>CYP3A4^∗1G</i> and <i>CYP3A5^∗3</i> polymorphisms on the pharmacokinetics and pharmcodynamics of ticagrelor in healthy Chinese subjects. The results indicated that the <i>CYP3A4^∗1G</i> polymorphism significantly influenced the pharmacokinetics of AR-C124910XX, and it may be more important than <i>CYP3A5^∗3</i> with respect to influencing ticagrelor pharmacokinetics by increasing CYP3A4 activity. However, the significant effect of <i>CYP3A4^∗1G</i> polymorphism on AR-C124910XX plasma levels did not translate into detectable effect on inhibition of platelet aggregation. Therefore, it seems not necessary to adjust the dosage of ticagrelor according to the <i>CYP3A4</i> or <i>3A5</i> genotype.