应用NLME程序建立丙戊酸在中国癫痫患儿中的群体药动学模型  

Establishment of population pharmacokinetics model of valproic acid in Chinese children with Epilepsy by using NLME program

作　　者：汪洋[1] 陈渝军[1] 张华年[1] 徐华[1] 刘茂昌[1] 高萍[1] 许琼[1] 

机构地区：[1]武汉市儿童医院,湖北武汉430016

出　　处：《中国医院药学杂志》2015年第14期1289-1294,共6页Chinese Journal of Hospital Pharmacy

摘　　要：目的:建立中国癫痫患儿口服丙戊酸的群体药动学模型,促进合理用药。方法:收集472例癫痫患儿口服丙戊酸后的血药浓度数据和临床资料。将患儿随机分成2组,PPK模型组(n=354):应用NLME程序建立一房室群体药动学模型(个体间变异采用指数模型,残差变异采用加法模型表示),考察各协变量对参数Ka、Vd和Cl的影响。用拟合优度、自举验证、直观预测检验(VPC)对最终模型的性能进行内部验证。PPK验证组(n=118):用最终模型预测验证组患儿的血药浓度,与实测值比较计算平均预测误差(MPE)、平均绝对预测误差(MAE)、平均预测误差平方(MSE)和均方根预测误差(RMSE)对最终模型进行外部验证。结果:PPK最终模型为:Ka=1.18×eηKa h-1;Vd=0.30×eηVd L·kg-1;Cl=0.008×(WT/18)-0.92×eηCl L·kg-1·h-1。体质量负相关影响Cl。拟合优度、自举验证和VPC的评价结果表明最终模型稳定、预测结果可靠。外部验证最终模型结果为:MPE=-0.09 mg·L-1,MAE=0.72 mg·L-1,MSE=0.76(mg·L-1)2,RMSE=0.87 mg·L-1。血药浓度实测值和最终模型的个体预测值(DV vs IPRED)的决定系数R2=0.998 1。外部验证说明最终模型预测准确度高。结论:本研究成功建立了中国癫痫患儿口服丙戊酸后的群体药动学模型。模型结构表明丙戊酸体重校正的清除率随患儿年龄和体质量的增加有下降趋势。OBJECTIVE To construct a population pharmacokinetics（PPK）model of valproic acid（VPA）in Chinese children with epilepsy and optimize rational use.METHODS Serum concentrations and clinical data were collected from472 cases of pediatric patients with epilepsy after VPA oral application.These patients were divided into two groups randomly including PPK model group（n=354）and PPK valid group（n=118）.NLME program was used to perform a population pharmacokinetics analysis based on model group data.One-compartment pharmacokinetic model was applied while exponential model was used to describe inter-individual variability and addition model to intra-individual variability.Covariates effects on the parameter Ka,Vd and Cl were investigated.Performance of final model was internally assessed by goodness-of-fit,Bootstrapping and visual predictive checking（VPC）.Concentrations of valid group patients were predicted by final model,and mean predicted error（MPE）,mean absolute prediction error（MAE）,mean squared prediction error（MSE）and root mean squared prediction error（RMSE）were calculated to externally assess final models.RESULTS Final model was as follows：Ka=1.18×e^ηKa h^-1;Vd=0.30×e^ηVd L·kg^-1;Cl=0.008×（WT/18）^-0.92×e^ηCl L·kg^-1·h^-1.Final model indicated a negative correlation of VPA clearance with body weight.Stability and predictive performance were accepted by goodness-of-fit,Bootstrapping and VPC.Externally assessed results of final model were MPE=0.09 mg·L^-1,MAE=0.72 mg·L^-1,MSE=0.76（mg·L^-1）2,RMSE=0.87mg·L^-1.The determination coefficient of observations（DV）-individual predicted value（IPRED）was 0.998 1 by the final model,which could predict VPA concentrations fairly well.CONCLUSION A PPK model of VPA oral application in Chinese children with epilepsy is successfully established in this study.The structure of final model indicates that weight-adjusted values of VPA clearance decrease with increasing age and body weight.

关 键 词：癫痫 儿童 丙戊酸 群体药动学 

分 类 号：R969.1[医药卫生—药理学]