奥卡西平在癫痫患者中的群体药动学研究

Population pharmacokinetics of oxcarbazepine in Chinese epilepsy patients

奥卡西平(OXC)是常用的新型抗癫痫药物。本研究前瞻性收集了184例癫痫患者的196份常规监测的OXC活性代谢产物10,11-二氢-10-羟基卡马西平(MHD)血药浓度和相关信息。采用非线性混合效应模型法(NONMEM),建立癫痫患者中OXC的群体药动学模型,并考察了性别、年龄、体重、合并用药及与OXC体内代谢相关的基因单核苷酸多态性(UGT2B7 c.802T>C、ABCC2 c.1249G>A、ABCC 23972C>T)对MHD药动学的影响。结果显示最终模型的药动学参数的群体典型值为:CL/F=1.84 L·h^(-1),V/F=275 L。性别和UGT2B7 c.802T>C对MHD体内清除率有显著性影响。CL/F的最终模型为:CL/F=1.84×0.848^(UGT2B7)×1.17^(GENDER)。公式中,若患者男性则GENDER=1,若为女性GENDER=0;UGT2B7 c.802T>C若为TT/TC型,则UGT2B7=1,若为CC型,则UGT2B7=0。此外,应用Bootstrap和正态预测分布误差法(NPDE)对建立的最终模型进行验证,结果显示建立的模型稳定、可靠。本研究首次应用NONMEM法考察了代谢酶和转运体的基因多态性对OXC药动学的影响,可为OXC的临床个体化给药提供参考依据。

Oxcarbazepine（OXC）is a common antiepileptic drugs.In this study,one hundred and eighty four epilepsy patients with 196 observations of oxcarbazepine＇s active metabolite,10,11-dihydro-10-monohydroxy carbazepine（MHD）were collected prospectively from routine clinical monitoring.Nonlinear mixed effect modeling was employed to develop a population pharmacokinetic model of oxcarbazepine in Chinese patients with epilepsy to investigate the impact of gender,age,weight,co-medications and genetic polymorphisms of UGT2B7 c.802T〉C,ABCC2 c.1249G〉A,ABCC 23972C〉T on pharmacokinetic characteristics of OXC.The population estimate of apparent clearance（CL/F）and apparent volume of distribution（V/F）was 1.84 L·h^-1 and275 L,respectively.Gender and UGT2B7 c.802TC affected the clearance rate of MHD significantly.The established model was：CL/F=1.84×0.848^UGT2B7×1.17^GENDER.Where the genotype of UGT2B7 c.802T〉C was CC,UGT2B7=0,otherwise UGT2B7=1.When the patient was male,GENDER=1,otherwise GENDER=0.The final model was evaluated by normalized predictive distribution error（NPDE）and bootstrap method.The model was stable and reliable,which offers a powerful approach for rational use of OXC in epilepsy patients.