基于丙戊酸群体药物动力学模型的个体化给药方案的制定

Formulation of personalized dosage regimen based on population pharmacokinetics of valproic acid

目的:建立丙戊酸在中国癫痫患儿体内的群体药物动力学模型,以制定个体化的给药方案。方法:回顾性收集2011年5月–2013年5月在我院住院并服用丙戊酸常规治疗癫痫患儿的临床资料与血药浓度数据,采用非线性混合效应模型法建立丙戊酸的群体药物动力学模型,基于最终的群体药动学模型,采用贝易斯反馈法估算个体参数并制定个体化的给药方案。结果:最终的群体模型为:CL/F=0.13+0.02×Age+0.04×LTG(L·h-1),V/F=7.40+23.4×Tablet(L),ka=2.38(h-1)。Age为年龄;当患儿同时服用拉莫三嗪时LTG为1,否则为0;当患儿服用丙戊酸片剂时Tablet为1,服用丙戊酸糖浆剂时Tablet为0。以此模型为基础的个体化预测结果与实测结果较为吻合。结论:建立的丙戊酸群体药物动力学模型具有一定的代表性,基于此模型采用贝易斯反馈法可用于个体化给药方案的制定。

Objective： To establish population pharmacokinetics of valproic acid （VPA） in children with epilepsy, and realize personalized dosage regimen on the basis of population pharmacokinetics. Methods： The clinical data and VPA plasma concentrations of children with epilepsy in our hospital from May 2011 to May 2013 were collected retrospectively, and nonlinear mixed effect modeling （NONMEM） method was used to establish population pharmacokinetics of VPA. A one compartment pharmacokinetic model with first-order absorption and elimination was used to characterize the concentration-time data. The first order conditional estimation with η-ε interaction （FOCE-I） was used throughout the model building procedure. Absorption rate constant （ka） was fixed as 2.38 （h1） according to previous report. On the basis of basic model, the influence of physiological factors and combined medication on relative clearance （CL/F） and apparent volume of distribution （V） were investigated using NONMEM program. Based on the final population pharmacokinetics and Bayesian method, the personalized dosage regimen was optimized. Results： A total of 113 pediatric inpatients and 205 plasma VPA concentrations were collected retrospectively. Objective function value of basic model and final model were 1 555.949 and 1 467.999, respectively. The final population parameters were as follow： CL/F = 0.13 ＋ 0.02 ×Age ＋ 0.04 × LTG （L·h-1）, V/F = 7.40 ＋ 23.4 × Tablet （L）, ka = 2.38 （h-1）. Where LTG was 1 when co-medicated with lamotrigine, otherwise LTG was 0. Where Tablet was 1 when patient took VPA tablets, otherwise Tablet was 0. A reliable results were got when using these parameters to predict the drug concentrations. Conclusion： The population pharmacokinetic model was proposed to estimate the individual CL/F and V for pediatric patients receiving VPA.