急性冠脉综合征患者氯吡格雷群体药动学-药效学结合模型研究  

Population pharmacokinetics and pharmacodynamics of clopidogrel in patients with acute coronary syndrome

作　　者：谢诚[1] 丁肖梁[1] 薛领[1] 蒋彬[2] 杭永付[1] 高杰[1] 缪丽燕[1] 

机构地区：[1]苏州大学附属第一医院药学部,江苏苏州215006 [2]苏州大学附属第一医院心血管内科,江苏苏州215006

出　　处：《药学学报》2014年第10期1426-1432,共7页Acta Pharmaceutica Sinica

基　　金：国家自然科学基金资助项目(81173132);江苏省医学重点人才资助项目(RC2011110);苏州市科技计划资助项目(SYS2011137)

摘　　要：本研究旨在急性冠脉综合征患者中建立氯吡格雷的群体药动学-药效学模型。通过前瞻性收集59例急性冠脉综合征患者,分别以氯吡格雷活性硫醇代谢产物和血小板VASP磷酸化水平作为其药动学和药效学指标,同时考察人口学指标、实验室指标、合并用药、临床合并症和相关代谢酶的遗传变异等因素,运用NONMEM软件对数据进行分析。药动学模型选择一般线性模型作为基础模型拟合数据,药效学模型选择间接效应模型-Turnover模型作为基础模型拟合数据。结果表明,氯吡格雷原药到活性硫醇代谢产物前体转化参数K12、活性硫醇代谢产物表观清除率(CL/F)和表观分布容积(V/F)的群体典型值分别为0.259 h-1、179 L·h-1和632 L,达最大药效一半时药效学参数EC50、药效生成参数Kin和最大药效参数Emax的群体典型值分别为1.57 ng·mL-1、4.29和0.664。最终模型显示,CYP2C19基因多态性对药动学模型中原药到活性硫醇代谢产物前体转化参数K12有影响,对临床合理使用氯吡格雷具有一定的参考意义。This study established a population pharmacokinetics-pharmacodynamics model of clopidogrel in patients with acute coronary syndrome. Fifty-nine patients were enrolled. The plasma concentration of clopidogrel active metabolite and vasodilator stimulated phosphoprotein platelet reactivity index （VASP-PRI） were selected as the pharmacokinetics index and the pharmacodynamics index, respectively. The covariates including demographic characteristics, laboratory indexes, combined medication, complications and genetic polymorphisms of related enzymes were screened for their influence on the pharmacokinetic and pharmacodynamics parameters. Population pharmacokinetic and pharmacodynamics data analysis was performed using NONMEM software. The general linear model and the indirectly effect model-turnover model for pharmacokinetic and pharmacodynamic analysis were selected as the basic model, respectively. The population typical values of K12, CL/F, V/F, EC50, Kin and Emax were 0.259 h^-1, 179 L·h^-1, 632 L, 1.57 ng·mL^-1, 4.29 and 0.664, respectively. CYP2C19 was the covariate in the final pharmacokinetic model, and the model was to design a prior dosage regimen.

关 键 词：氯吡格雷 急性冠脉综合征 群体药动学 群体药效学 

分 类 号：R969[医药卫生—药理学]