刘萌, 马春来, 焦正, 高玉成, 刘艺茜, 吴洵昳. 奥卡西平在癫痫患者中的群体药动学研究J. 药学学报, 2018,53(8): 1318-1323. doi: 10.16438/j.0513-4870.2018-0187
引用本文: 刘萌, 马春来, 焦正, 高玉成, 刘艺茜, 吴洵昳. 奥卡西平在癫痫患者中的群体药动学研究J. 药学学报, 2018,53(8): 1318-1323. doi: 10.16438/j.0513-4870.2018-0187
LIU Meng, MA Chun-lai, JIAO Zheng, GAO Yu-cheng, LIU Yi-xi, WU Xun-yi. Population pharmacokinetics of oxcarbazepine in Chinese epilepsy patientsJ. Acta Pharmaceutica Sinica, 2018,53(8): 1318-1323. doi: 10.16438/j.0513-4870.2018-0187
Citation: LIU Meng, MA Chun-lai, JIAO Zheng, GAO Yu-cheng, LIU Yi-xi, WU Xun-yi. Population pharmacokinetics of oxcarbazepine in Chinese epilepsy patientsJ. Acta Pharmaceutica Sinica, 2018,53(8): 1318-1323. doi: 10.16438/j.0513-4870.2018-0187

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

  • 摘要: 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 >CABCC2 c.1249G >AABCC 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-1V/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=1.84×0.848UGT2B7×1.17GENDER。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。

     

    Abstract: 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 and 275 L, respectively. Gender and UGT2B7 c.802T>C affected the clearance rate of MHD significantly. The established model was:CL/F=1.84×0.848UGT2B7×1.17GENDER. 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.

     

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