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

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

JOURNAL=Frontiers in Pharmacology

VOLUME=10

YEAR=2019

URL=https://www.frontiersin.org/journals/pharmacology/articles/10.3389/fphar.2019.00209

DOI=10.3389/fphar.2019.00209

ISSN=1663-9812

ABSTRACT=<p><bold>Objectives:</bold> 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.</p><p><bold>Methods:</bold> 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 <italic>CYP2C19</italic><sup>*</sup><italic>2, CYP2C19</italic><sup>*</sup><italic>3, CYP3A5</italic><sup>*</sup><italic>3, UGT1A1</italic><sup>*</sup><italic>6, UGT1A1</italic><sup>*</sup><italic>28, UGT2B7</italic><sup>*</sup><italic>2, UGT2B7</italic><sup>*</sup><italic>3, SLCO1B1</italic> 388A&gt;G, and <italic>SLCO1B1</italic> 521T&gt;C, on the pharmacokinetics of ticagrelor and M8, and platelet function recovery were investigated.</p><p><bold>Results:</bold> The time to recover 50% of the maximum drug effect (RT<sub>50</sub>) ranging from 36 to 126 h with 46.9% CV had a remarkable individual difference and was positively associated with the half-life (t<sub>1/2</sub>) of M8 (<italic>r</italic> = 0.3901, <italic>P</italic> = 0.0067). The time of peak concentration (T<sub>max</sub>) of ticagrelor for CYP2C19<sup>*</sup>3 GG homozygotes was significantly higher than that of GA heterozygotes (<italic>P</italic> = 0.0027, <italic>FDR</italic> = 0.0243). Decreased peak concentration (C<sub>max</sub>) of M8 was significantly associated with <italic>SLCO1B1</italic> 388A&gt;G A allele (<italic>P</italic> = 0.0152, <italic>FDR</italic> = 0.1368). <italic>CYP2C19</italic><sup>*</sup><italic>2</italic> A was significantly related to decreased C<sub>max</sub> of M8 (<italic>P</italic> = 0.0455, <italic>FDR</italic> = 0.2048). While, the influence of these nine SNPs on the recovery of platelet function was not significant.</p><p><bold>Conclusion:</bold> 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.</p><p><bold>Clinical Trial Registration:</bold><ext-link ext-link-type="uri" xlink:href="https://clinicaltrials.gov/ct2/show/NCT03092076" xmlns:xlink="http://www.w3.org/1999/xlink">https://clinicaltrials.gov/ct2/show/NCT03092076</ext-link>, identifier: NCT03092076</p>