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

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

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://ichgcp.net/clinical-trials-registry/NCT03092076, identifier: NCT03092076.

Keywords: genetic variants; healthy subjects; pharmacokinetics; recovery of platelet function; ticagrelor.

Figures

Figure 1
Figure 1
Pharmacokinetic profiles of ticagrelor and M8 in 51 healthy subjects.
Figure 2
Figure 2
Average platelet aggregation after a single dose of ticagrelor in healthy subjects. (A) Average platelet aggregation during 0–48 h after a single 180 mg oral dose of ticagrelor (mean ± SD); (B) average platelet aggregation within all points of time after a single 180 mg oral dose of ticagrelor (mean ± SD).
Figure 3
Figure 3
Sigmoid maximal effect model of platelet aggregation. Goodness of fit plots: (A) Observed vs. individual population predicted values; (B) individual weighted residuals vs. time; (C) scatter plot of time vs. platelet aggregation, and the prediction curve.
Figure 4
Figure 4
Association of half-life of ticagrelor and M8 with recovery of platelet function. (A) Association of half-life (t1/2) of ticagrelor with the time to recover 50% of the maximum drug effect (RT50); (B) association of t1/2 of M8 with RT50; (C) association of t1/2 of ticagrelor with the recovery day to the baseline platelet aggregation (RECDAY); (D) association of t1/2 of M8 with the RECDAY.

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