瑞舒伐他汀钙治疗中国高脂血症人群的药效动力学探索  

An exploring study on the pharmacodynamics of rosuvastatin in Chinese hypercholesterolemic patients

作　　者：杨娟[1] 李禄金[1] 何迎春[1] 许羚[1] 吕映华[1] 张密[1] 刘红霞[1] 郑青山[1] 

机构地区：[1]上海中医药大学药物临床研究中心,上海201203

出　　处：《中国临床药理学与治疗学》2010年第8期894-900,共7页Chinese Journal of Clinical Pharmacology and Therapeutics

基　　金：上海市教委重点学科建设项目(J50303);上海市高校E研究院项目(E0308);2007年上海高校选拔培养优秀青年教师科研专项基金资助(SZY07027)

摘　　要：目的:建立舒伐他汀钙治疗中国高脂血症人群的群体药效学模型,考察单位体重用药剂量和低密度脂蛋白胆固醇(LDL-C)的量效关系。方法:从已有的临床研究中,选择合适的受试者,提取其主要疗效指标(服用瑞舒伐他汀钙8周后LDL-C下降率),及潜在的可能对LDL-C下降率有影响的指标(包括受试者所属试验、年龄、性别、体重和LDL-C基线值等)。用NONMEM软件进行模型拟合和群体药效学参数的估算。用Bootstrap法和蒙特卡洛模拟法分别对最终群体药效学模型进行验证和预测。结果:SigmoidalEmax药效学模型较好地拟合了瑞舒伐他汀钙治疗中国高脂血症人群的量效关系,所属试验、年龄、性别、体重和LDL-C基线值等因素对其无影响,最终模型的药效学参数Emax、ED50和γ分别为53.9%,0.072mg/kg和3.76,且参数的相对标准误均较小。Bootstrap法证明了最终模型具有较好的稳定性,蒙特卡洛模拟预测药效的95%可信区间包含了约50%受试者的实测药效。结论:本研究用群体分析方法建立了中国高脂血症人群应用瑞舒伐他汀钙的药效学模型,反映了约50%受试者用药后的药效学特征,说明除剂量外,影响药效因素众多,有待进一步探索。AIM：To develop a population pharmacodynamic（PPD）model for investigating the relationship between dose per kilogram body weight of rosuvastatin and LDL-C reduction in Chinese hypercholesterolemic patients.METHODS：Eligible patients were selected from relevant clinical trials and end point data were extracted for each patient.The primary efficacy end point was the mean percentage of change in LDL-C at 8 weeks from baseline.Potential covariates including trial,age,gender,body weight and baseline LDL-C levels were collected.Population modeling was performed with NONMEM.Bootstrap and Monte Carlo simulation was performed to assess the model robustness and prediction,respectively.RESULTS：Sigmoidal Emax model successfully described the dose-response relationship of rosuvastatin in Chinese hyperlipoidemic patients.The covariates did not significantly influence any hypercholesterolemic parameters.The population parameter estimates of Emax,ED50 and gamma were 53.9%,0.072 mg/kg and 3.76,and their relative standard errors were all small.Model robustness was validated by a nonparametric bootstrap.The 95% confidence interval of Monte Carlo simulation included about 50% patients＇ observed values of LDL-C reduction.CONCLUSION：This study developed a pharmacodynamic model for rosuvastatin in Chinese hypercholesterolemic patients with population method which described the pharmacodynamic characteristic of about 50% patients.The result indicates LDL-C reduction of rosuvastatin may be impacted by numerous factors except for dose,which should be investigated further.

关 键 词：瑞舒伐他汀钙 LDL-C下降率 群体药效学 NONMEM 

分 类 号：R311[医药卫生—基础医学]