用模型和模拟方法设计氨氯地平的群体药动学研究方案  

Modeling and simulation activities to design sampling scheme for population pharmacokinetic study on amlodipine

作　　者：左笑丛[1] 袁洪[1] 张毕奎[1] Chee M.NG Jeff S.BARRETT 阳国平[1] 黄志军[1] 裴奇[1] 郭韧[1] 周亚男[1] 荆宁宁[1] DI Wu 

机构地区：[1]中南大学湘雅三医院,湖南长沙410013 [2]美国费城儿童医院临床药物治疗系应用药动学/药效学研究室,PA19104

出　　处：《药学学报》2012年第7期941-946,共6页Acta Pharmaceutica Sinica

基　　金：重大基础研究(973)前期研究专项基金项目(2011CB512001);国家自然科学基金资助项目(81102512);教育部博士点基金资助项目(20110162120023);湖南省国际合作科技计划重点项目(2010WK2006)

摘　　要：合理的采样设计是建立可靠群体药动学模型的重要基础。应用非线性混合效应模型的群体药动学研究,是一种有效利用稀疏血样数据估算群体药动学参数的方法。本研究根据D最优化设计和贝叶斯法设计采样方案。以已报道的氨氯地平群体药动学模型为基础,根据临床研究的目的、给药方案和随访时间等设计几套采样方案,采用WinPOPT软件计算优化采样方案,用蒙特卡罗法(Monte Carlo)对各优化的采样方案分别建立一套含400个患者的NONMEM数据文件,用NONMEM7.2软件模拟氨氯地平的浓度数据,然后估算其重要药动学参数(CL/F,V/F和Ka),并计算其平均预测误差(MPE)和平均绝对预测误差(MAPE)。在6个采样方案中,以方案6和3对CL/F估算的准确度和精密度较优,MPE分别为0.1%和0.6%,MAPE均为0.7%。对V的估算,各采样方案间无明显差异。因此,选用氨氯地平拟合药动学参数的准确度和精密度较优,且采样点个数较少的方案3为最佳临床研究方案。本研究旨在为开展氨氯地平在肾功能损害合并高血压患者的群体药动学研究提供科学、有效的采样方法,为群体PK/PD研究提供一种优化设计临床研究方案的科学方法。Reasonable sampling scheme is the important basis for establishing reliable population pharmacokinetic model. It is an effective method for estimation of population pharmacokinetic parameters with sparse data to perform population pharmacokinetic analysis using the nonlinear mixed-effects models. We designed the sampling scheme for amlodipine based on D-optimal sampling strategy and Bayesian estimation method. First, optimized sample scenarios were designed using WinPOPT software according to the aim, dosage regimen and visit schedule of the clinical study protocol, and the amlodipine population model reported by Rohatagi et al. Second, we created a NONMEM-formatted dataset （n = 400） for each sample scenario via Monte Carlo simulation. Third, the estimation of amlodipine pharmacokinetic parameters （clearance （CL/F）, volume （V/F） and Ka） was based on the simulation results. All modeling and simulation exercises were conducted with NONMEM version 7.2. Finally, the accuracy and precision of the estimated parameters were evaluated using the mean prediction error （MPE） and the mean absolute error （MAPE）, respectively. Among the 6 schemes, schemes 6 and 3 have good accuracy and precision. MPE is 0.1% for scheme 6 and -0.6% for scheme 3, respectively. MAPE is 0.7% for both schemes. There is no significant difference in MPE and MAPE of volume among them. Therefore, we select scheme 3 as the final sample scenario because it has good accuracy and precision and less sample points. This research aims to provide scientific and effective sampling scheme for population pharmacokinetic （PK） study of amlodipine in patients with renal impairment and hypertension, provide a scientific method for an optimum design in clinical population PK/PD （pharmacodynamics） research.

关 键 词：氨氯地平 群体药动学 模型和模拟 方案设计 

分 类 号：R969[医药卫生—药理学]