Department of Pharmacy, Peking University First Hospital, No. 6, Dahongluochang Street, Xicheng District, Beijing, 100034, China.
School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, China.
Clin Drug Investig. 2022 May;42(5):447-458. doi: 10.1007/s40261-022-01154-6. Epub 2022 Apr 30.
The search for potential gene loci that affect the pharmacodynamics and pharmacokinetics of ticagrelor is a matter of broad clinical interest. The objective of this study was to investigate the effect of genetic polymorphisms on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy Chinese subjects.
This is a multi-center study in China, including three hospitals from Beijing, Nanchang, and Changsha. Healthy Chinese subjects aged 18-45 years with unknown genotypes were included. All subjects received a single oral dose of 90 mg of ticagrelor. Platelet aggregation and the area under the concentration-time curve for ticagrelor and its major active metabolite in plasma samples were assessed. Genome-wide association studies and candidate gene association analysis related to ticagrelor were performed.
One hundred and seventy-five native Chinese subjects were enrolled and completed the study. According to the p value, the threshold of ticagrelor population was 6.57 × 10 (0.05/76106), one single-nucleotide polymorphism chr6:17616513 of gene NUP153 (p = 2.03 × 10) related to the area under the concentration-time curve for plasma concentration at time zero versus the last measurable timepoint, and one single nucleotide polymorphism rs17204533 of gene SVEP1 (p = 3.96 × 10) related to P2Y12 reaction unit of ticagrelor was identified. In addition, L1TD1, CETP, CLEC2A, CHSY1, PDZRN3, CTU2, PIEZO1, APOBEC1, SEMA6A, KAZN, and FASN polymorphisms might influence the pharmacokinetics of ticagrelor, while PARP10, TRIB1, CYP2C19, and UGT2B7 might affected its pharmacodynamics.
Genetic variation affects the pharmacokinetics and pharmacodynamics of ticagrelor in healthy individuals. The detection of NUP153, SVEP1 gene variation will be helpful for pharmacodynamic prediction and evaluation, and the regulation of these genes may be the target of new drug development. Further studies are required to confirm the results and explore whether these single-nucleotide polymorphisms are associated only with platelet activity or also with cardiovascular events and all-cause mortality.
NCT03161002.
寻找影响替格瑞洛药效学和药代动力学的潜在基因座是一个具有广泛临床意义的问题。本研究旨在探讨遗传多态性对健康中国受试者替格瑞洛药代动力学和药效学的影响。
这是一项在中国进行的多中心研究，包括来自北京、南昌和长沙的三家医院。纳入了年龄在 18-45 岁且基因型未知的健康中国受试者。所有受试者均单次口服 90mg 替格瑞洛。评估替格瑞洛及其主要活性代谢物在血浆样本中的血小板聚集和浓度-时间曲线下面积。进行了与替格瑞洛相关的全基因组关联研究和候选基因关联分析。
共纳入 175 名中国本地受试者，均完成了研究。根据 p 值，替格瑞洛人群的阈值为 6.57×10(-5)/76106，基因 NUP153 的 chr6：17616513 处的一个单核苷酸多态性（p=2.03×10）与血浆浓度从零时刻到最后可测量时间点的浓度-时间曲线下面积有关，以及基因 SVEP1 的 rs17204533 处的一个单核苷酸多态性（p=3.96×10）与替格瑞洛的 P2Y12 反应单位有关。此外，L1TD1、CETP、CLEC2A、CHSY1、PDZRN3、CTU2、PIEZ01、APOBEC1、SEMA6A、KAZN 和 FASN 多态性可能影响替格瑞洛的药代动力学，而 PARP10、TRIB1、CYP2C19 和 UGT2B7 可能影响其药效学。
遗传变异影响健康个体替格瑞洛的药代动力学和药效学。检测 NUP153、SVEP1 基因变异有助于预测和评估药效学，调节这些基因可能是新药开发的目标。需要进一步研究来确认这些结果，并探讨这些单核苷酸多态性是否仅与血小板活性有关，还是与心血管事件和全因死亡率有关。
NCT03161002。
