替格瑞洛在中国健康男性志愿者中的药动学及药效学研究

Pharmacokinetics and pharmacodynamics of ticagrelor in Chinese healthy male volunteers

目的:研究替格瑞洛在中国健康志愿者中药动学及药效学,为其临床合理使用提供依据。方法:选14名健康男性志愿者,分别单次口服替格瑞洛180 mg,在不同时间点采集血样分别用于药动力学及药效学研究,其中药动学采样时间点为给药前、给药后0.5,1,1.5,2,3,4,5,6,8,12,16,24,36,48 h,药效学采样时间点为给药前他和给药后1,2,4,12,24,48 h,药动学血浆样品采用蛋白沉淀法处理,超高效液相色谱-串联质谱(UPLC-MS/MS)法测定原药、活性代谢产物浓度;药效学采用四通道血小板聚集仪测定ADP诱导的血小板聚集率,以血小板聚集抑制的变化程度作为替格瑞洛的药效学指标。用WinNonlin软件处理所得数据。结果:14例健康受试者口服180 mg替格瑞洛后,替格瑞洛原药、活性代谢产物AR-C124910XX在人体内平均tmax分别为(1.9±0.6)h和(2.1±0.6)h,平均t1/2分别为(8.3±1.1)h和(9.7±2.5)h,平均Cmax分别为(1 447.0±532.2)ng·mL^(-1)和(384.5±90.2)ng·mL^(-1),平均AUC0-last为(9 023.0±3 285.4)ng·mL^(-1)·h和(3 445.0±723.2)ng·mL-1·h,平均AUC0-∞为(9 208.7±3 437.6)ng·mL^(-1)·h和(3 594.4±827.0)ng·mL^(-1)·h。替格瑞洛对血小板抑制的达峰时间为4h,对血小板抑制的最大效应Emax为(75.9±11.9%)。替格瑞洛的抗血小板效应随替格瑞洛及AR-C124910XX降低而减弱。结论:本研究系统考察了14例健康志愿者服用替格瑞洛后的药动学及药效学,为临床使用替格瑞洛剂量调整、优化治疗方案提供了理论依据。

OBJECTIVE To study pharmacokinetics and pharmacodynamics of ticagrelor in Chinese healthy male volunteers,provide a theoretical basis for optimization of ticagrelor treatment.METHODS A single oral dose of 180 mg ticagrelor in tablet formulation was given to 14 healthy male volunteers in a random study.Blood samples for pharmacokinetics analyses were collected immediately before and at 0.5,1,1.5,2,3,4,5,6,8,12,16,24,36 h and 48 h after drug administration.Pharmacodynamics samples were collected before and at 1,2,4,12,24 h and48 h after drug administration.Plasma concentrations of ticagrelor and its active metabolite,AR-C124910 XX,were measured using UPLC-MS-MS.Inhibition of platelet aggregation was determined by aplatelet aggregation profiler-4 optical aggregometer after induction with 5μmol·L-1of adenosine diphosphate.Inhibitory effects on ADP-induced platelet aggregation（IPA）were used as the primary pharmacodynamics parameter.RESULTS Following a single oral dose of 180 mg,ticagrelor was rapidly absorbed.Meantmaxwas 1.9 hours,and meant1/2was approximately 8.3 hours.Mean Cmax,AUC0-lastand AUC0-∞ for ticagrelor were（1 447.0±532.2）ng·mL-1,（9 023.0±3 285.4）ng·mL-1·h and（9 208.7±3 437.6）ng·mL-1·h,respectively.Major metabolite AR-C124910 XX was rapidly formed after a single ticagrelor dose.Mean tmaxand mean t1/2for AR-C124910 XX were 2.1 hours and 9.7 hours,respectively.Mean Cmax,AUC0-lastand AUC0-∞ for AR-C124910 XX were（384.5±90.2）ng·mL-1,（3 445.0±723.2）ng·mL-1·h and（3 594.4±827.0）ng·mL-1·h,respectively.Strong inhibition of platelet aggregation was shown after administration of ticagrelor with a tmaxof 4 h and Emaxof（75.9±11.9）%.IPA gradually decreased with declining plasma concentrations of ticagrelor and AR-C124910 XX,indicating that ticagrelor-associated IPA was concentration dependent and slowly reversible.CONCLUSION The study has systematically evaluated pharmacokinetics and pharmacodynamics of ticagrelor in healthy male volunteers by administering a single oral dose,providing a theoretical basis for dose adjustment and optimization of ticagrelor in clinical practice.