左乙拉西坦在癫痫患儿中的群体药动学研究  

Population pharmacokinetics study of levetiracetam in pediatric patients with epilepsy

作　　者：汪洋[1] 张华年[1] 徐华[1] 陈渝军[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：《中国新药与临床杂志》2015年第3期184-190,共7页Chinese Journal of New Drugs and Clinical Remedies

摘　　要：目的建立癫痫患儿口服左乙拉西坦的群体药动学(PPK)模型,并用此模型探讨左乙拉西坦在儿童患者群体内的药动学特征。方法收集344例癫痫患儿口服左乙拉西坦后的血药浓度数据和临床资料。将患儿随机分为两组,模型组(n=259)采用NLME程序进行PPK分析,建立一房室药动学模型(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、自举法对最终模型的性能进行内部验证。采用最终模型预测验证组(n=85)患儿的血药浓度,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(h-1)=1.01×eηKa,Vd(L·kg-1)=[0.42+0.000 35×(AGE-56)]×eηVd,CL(L·kg-1·h-1)=[0.05-0.009 5×(ln WT-2.83)]×eηCl;年龄(AGE)正相关影响Vd,体重的自然对数值(ln WT)负相关影响CL。拟合优度、自举验证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=0.01 mg·L-1,MAE=0.91 mg·L-1,MSE=1.16(mg·L-1)2,RMSE=1.08 mg·L-1。血药浓度实测值和最终模型的个体预测值的决定系数R2=0.990 6。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癫痫患儿口服左乙拉西坦后的PPK模型,模型结构表明左乙拉西坦体重校正的清除率随患儿年龄和体重的增加有下降趋势。AIM To set up a population pharmacokinetics（PPK） model of levetiracetam in pediatric patients with epilepsy and to investigate the pharmacokinetic characteristics of levetiracetam in these subpopulations.METHODS Serum concentrations and clinical data from 344 pediatric patients with epilepsy after levetiracetam oral application were collected.These patients were divided into two groups randomly,as model group（n = 259） and valid group（n = 85）.Using NLME software to carry out a PPK analyses based on the model group data.One-compartment pharmacokinetic model was applied while the exponential model was used to describe the inter-individual variability and addition model to the intra-individual variability.Covariates effect on the parameter Ka,Vdand CL were investigated.The performance of final model was internal assessed by goodness-of-fit and bootstrapping.The concentrations of the valid group patients were predicted by final model,and the mean predicted error（MPE）,mean absolute prediction error（MAE）,mean squared prediction error（MSE）,root mean squared prediction error（RMSE） were calculated to external assess the final model.RESULTS The final model were as follows：Ka（h-1） = 1.01 × eηKa,Vd（L·kg-1） = [0.42 ＋ 0.000 35 ×（AGE-56）] × eηVd,Cl（L·kg-1·h-1） = [0.05-0.009 5 ×（ln WT-2.83）] × eηCl.The final model indicated a positive correlation of Vdwith age and a negative correlation of CL with natural logarithm of body weight.The stability and the predictive performance were accepted by goodness-of-fit and bootstrapping.The external assessed results of final model were MPE = 0.01 mg·L-1,MAE = 0.91 mg·L-1,MSE = 1.16（mg·L-1）2,RMSE =1.08 mg·L-1.The determination coefficient of observations（DV）-individual predicted value（IPRED） by the final model was 0.990 6,which could predict the levetiracetam concentrations fairly well.CONCLUSION A PPK model of levetiracetam oral application in pediatric patients with epilepsy is successfully established in this stu

关 键 词：癫痫 儿童 左乙拉西坦 群体药动学 

分 类 号：R971.6[医药卫生—药品]