用非线性混合效应模型法建立癫痫儿童拉莫三嗪的群体药代动力学模型  

Population pharmacokinetics model of lamotrigine in epileptic children by nonlinear mixed effects modeling

作　　者：陈亚南[1] 邱枫[1] 徐善森 张媞[1] 杨帆[1] 肇丽梅[1] 

机构地区：[1]中国医科大学附属盛京医院药学部,沈阳110004

出　　处：《中国临床药理学杂志》2016年第17期1610-1613,共4页The Chinese Journal of Clinical Pharmacology

基　　金：国家自然科学基金资助项目(81302857);辽宁省自然科学基金资助项目(2013021079)

摘　　要：目的用非线性混合效应模型(NONMEM)方法建立拉莫三嗪在癫痫儿童中的群体药代动力学模型。方法回顾性收集140例服用拉莫三嗪的癫痫患儿(1~16岁)的165份血药浓度数据及临床资料。血药浓度为临床常规监测的稳态浓度,用高效液相色谱法测定。用NONMEM及辅助软件建立癫痫儿童的群体药代动力学模型,用自举法和正态化预测分布误差(NPDE)评估模型参数的精确度。结果建立的最终回归模型为全身清除率(CL/F)=1.60×(WT/40)0.79×e^(-1.25×TAMT1/500)×4.25^(CBZ),分布容积(V/F)=330×(TAMT/100)^(5.26×0.1),CL/F、V/F的群体典型值分别为1.60 L·h^(-1)和330 L。结论用NONMEM法初步建立了拉莫三嗪在癫痫儿童的群体药代动力学模型,可用于预测血药浓度。Objective To establish the population pharmacokinetics （PPK） of lamotrigine （LTG） in epilepstie children using a nonlinear mixed effects modeling （NONMEM） approach. Methods LTG steady -state plasma concentration data from therapeutic drug monitoring were collected retrospectively from 140 epileptic patients （age from 1 -16 years）, with a total of 165 plasma drug concentrations. LTG concentra- tions were determined using a HPLC method. Data were modeled, and the final model was evaluated using NONMEM and auxiliary software tools. A bootstrap sampling method and normalized prediction distribution errors （NPDE） were applied to estimate the precision of the final model parameter values. Results The final regression model for LTG was as follows： clearance （CL/F） = 1.60 × （ WT/40）×79 × e-1.25×TAMT1/500×4.25cBz, volume of distribution （V/F） = 330 × （TAMT/100）526×0.1 And the population typical values of CL/F and V/F were 1.60 L· h- 1 and 330 L respectively in the final model. Conclusion This study prelimi- narily established PPK model of LTG in the epileptic children. LTG concen- trations can be predicted by this model. And the model may be a more relia- ble method for individualizing the LTG dosing regimen in epileptic children.

关 键 词：拉莫三嗪 癫痫 群体药代动力学 非线性混合效应模型法 

分 类 号：R971.6[医药卫生—药品]