用NONMEM法建立癫痫患者丙戊酸群体药代动力学模型  

Population Pharmacokinetics Model of Valproate in Epilepsy Patients by NONMEM

作　　者：王化明[1,2] 赖萍[3] 谢娟[4] 

机构地区：[1]暨南大学医学院第三附属医院 [2]珠海市人民医院药剂科,广东珠海519000 [3]内江市第二人民医院药剂科,四川内江641000 [4]贵州省人民医院药剂科,贵州贵阳550002

出　　处：《今日药学》2012年第1期1-6,共6页Pharmacy Today

基　　金：广东省医院药学研究基金(编号:2011A22);贵州省自然科学基金(黔科合J字[2006]2058号)

摘　　要：目的建立丙戊酸(VPA)在癫痫患者中的群体药代动力学(PPK)模型,考察固定效应因素对VPA清除率(CL/F)的影响。方法回顾性收集贵州省人民医院111名癫痫患者VPA稳态血药浓度数据及相应的人口学、合并用药及CYP2A6基因型等资料,随机将患者分成建模组(74名)及验证组(37名),使用建模组数据通过非线性混合效应模型(NONMEM)程序建立VPA的PPK模型。使用验证组数据来验证模型的准确度和精密度,比较基础模型和最终模型的平均预测误差(MPE)、平均绝对误差(MAE)、平均根方差(RMSE)。结果建立的最终模型包含了日用药剂量(DDO)及CYP2A6基因型,模型方程为:CL/F=0.363.DDO0.525.1.29GENECYP2A6。最终模型有更好的精密度及准确度,基础模型MPE、MAE、RMSE值为-10.631、4.40、22.55,最终模型相应值为-6.11、9.06、14.17。结论本研究初步建立癫痫患者VPA的PPK模型,VPA清除率随日给药剂量的增大而增大,CYP2A6野生型(CYP2A6*1/*1)组患者较CYP2A6突变型(CYP2A6*1/*4、CYP2A6*4/*4)组患者有更高的VPA清除率。Objective To establish valproate（VPA） population pharmacokinetic（PPK） model in epilepsy patients and study the effect of fixed effect factors on VPA clearance（CL/F）.Methods A total of 111 epileptic patients VPA steady-state serum concentration data and the corresponding demography,combination drugs and CYP2A6 gene polymorphism were retrospectively collected at Guizhou Provincial People＇s Hospital.The patients were randomly divided into PPK-model group（n=74） and PPK-valid group（n=37）.Population pharmacokinetic model of VPA was established by NONMEM（Nonlinear mixed-effect model） program with PPK-model group data.To assess the accuracy and precision of the basic models and the final model with PPK-valid group data,the average prediction error（MPE）,average absolute error（MAE）,and average root variance（RMSE） were calculated.These values were compared.Results The final population pharmacokinetic model of VPA in epileptic patients included daily does（DDO） and CYP2A6 gene polymorphism.The regression was CL/F=0.363·DDO0.525·1.29GENECYP2A6The final model had better precision and accuracy than the basic model,and the values of the basic model MPE,MAE,RMSE were 10.63,14.40,22.55,and the values of the final model were-6.11,9.06,14.17,respectively.Conclusion This study preliminary established PPK model of VPA in epileptic patients.The clearance rate increases with the daily dose.Compared with CYP2A6 mutations（CYP2A6＊1/＊4,CYP2A6＊4/＊4）,CYP2A6 wild-type（CYP2A6＊1/＊1） patients have higher clearance rate.

关 键 词：丙戊酸 群体药代动力学 CYP2A6 癫痫 

分 类 号：R965[医药卫生—药理学]