Pharmacokinetic and Pharmacogenetic Factors Contributing to Platelet Function Recovery After Single Dose of Ticagrelor in Healthy Subjects.

Qian Zhu,Liping Mai,Wanping Zhong,Lan Tang,Jiyan Chen,Shuwen Liu,Xipei Wang,Weihua Lai,Guodong He,Shilong Zhong

doi:10.3389/fphar.2019.00209

Abstract

Objectives: This study aimed to elucidate the contribution of candidate single nucleotide polymorphisms (SNPs) related to pharmacokinetics on the recovery of platelet function after single dose of ticagrelor was orally administered to healthy Chinese subjects.Methods: The pharmacokinetic profiles of ticagrelor and its metabolite AR-C124910XX (M8), and the platelet aggregation (PA), were assessed after 180 mg of single-dose ticagrelor was orally administered to 51 healthy Chinese subjects. Effects of CYP2C19*2, CYP2C19*3, CYP3A5*3, UGT1A1*6, UGT1A1*28, UGT2B7*2, UGT2B7*3, SLCO1B1 388A>G, and SLCO1B1 521T>C, on the pharmacokinetics of ticagrelor and M8, and platelet function recovery were investigated.Results: The time to recover 50% of the maximum drug effect (RT50) ranging from 36 to 126 h with 46.9% CV had a remarkable individual difference and was positively associated with the half-life (t1/2) of M8 (r = 0.3901, P = 0.0067). The time of peak concentration (Tmax) of ticagrelor for CYP2C19*3 GG homozygotes was significantly higher than that of GA heterozygotes (P = 0.0027, FDR = 0.0243). Decreased peak concentration (Cmax) of M8 was significantly associated with SLCO1B1 388A>G A allele (P = 0.0152, FDR = 0.1368). CYP2C19*2 A was significantly related to decreased Cmax of M8 (P = 0.0455, FDR = 0.2048). While, the influence of these nine SNPs on the recovery of platelet function was not significant.Conclusion: Our study suggests that the elimination of M8 is an important factor in determining the recovery of platelet function. Although CYP2C19 and SLCO1B1 genetic variants were related to the pharmacokinetics of ticagrelor or M8, they did not show a significant effect on the platelet function recovery in this study.Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT03092076, identifier: NCT03092076

Highlights

Ticagrelor, a member of a novel chemical class of antiplatelets, is the first reversibly binding, noncompetitive, orally bioavailable P2Y12 receptor antagonist that acts directly without requiring metabolic activation (James et al, 2009; Teng et al, 2010; Wiviott and Steg, 2015)
CYP2C19 and SLCO1B1 genetic variants were related to the pharmacokinetics of ticagrelor or M8, they did not show a significant effect on the platelet function recovery in this study
CYP2C19 and SLCO1B1 genetic variants were related to the pharmacokinetics of ticagrelor and M8, no statistically significant difference was observed in the recovery of the platelet activity of these candidate single nucleotide polymorphisms (SNPs) (P > 0.05)

Summary

Introduction

Ticagrelor, a member of a novel chemical class of antiplatelets, is the first reversibly binding, noncompetitive, orally bioavailable P2Y12 receptor antagonist that acts directly without requiring metabolic activation (James et al, 2009; Teng et al, 2010; Wiviott and Steg, 2015). Ticagrelor is recommended as an antiplatelet therapy for patients with acute coronary syndrome (ACS) according to several guidelines (Wallentin et al, 2009; Levine et al, 2016). Patients treated with ticagrelor awaiting CABG are associated with an increased risk of perioperative bleeding complications (Hansson et al, 2016). This issue is important for patients who need urgent surgical procedures, such as CABG. Shortened discontinuation interval before surgery, which may increase the bleeding risk, and the optimal time of terminating the ticagrelor treatment before cardiac surgery is controversial

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