NONMEM法探索CYP1A2对儿童卡马西平群体药动学的影响

Exploring the Impact of CYP1A2 on Carbamazepine Population Pharmacokinetics Using NONMEM Approach

关键词:  卡马西平  癫痫患儿  群体药动学  非线性混合效应模型  CYP1A2

Key words:  carbamazepine  epileptic children  population pharmacokinetics  nonlinear mixed effects modeling  CYP1A2

摘要:

目的 用非线性混合效应模型法探索CYP1A2对儿童卡马西平群体药动学的影响。方法 回顾性收集180名癫痫患儿的临床资料及720个卡马西平血药浓度监测数据，采用非线性混合效应模型法估算群体药动学参数并建立模型，采用图形法和可视化预测检验的方法对最终模型进行验证。结果 建立了该药物的一级吸收一室模型，最终模型参数如下：CL=3.25×（WT/29.8）^0.22×e^{0.05（AA=1）}×e^ηCL（L·h^-1），V_d=34.78×e^ηVd（L），K_a=1.2·h^-1。当CYP1A2-163为AA时，AA=1；当CYP1A2-163为CA或CC时，AA=0。患儿体质量的增长可以导致药物清除率的非线性增加，CYP1A2-163C>A突变可加快卡马西平的清除。结论 患儿的体质量与CYP1A2基因突变（-163C>A）对CL有显著影响，在用药前建议考虑患者体质量与CYP1A2基因型。

Abstract:

OBJECTIVE To investigate the impact of CYP1A2 on the population pharmacokinetics of carbamazepine in Chinese epileptic children by means of the nonlinear mixed-effects approach. METHODS A total of 720 carbamazepine blood monitoring data and their clinical data were collected retrospectively from 180 children with epilepsy. The population pharmacokinetics were estimated by Phoenix NLME software and the model was conducted. Internal model validation by goodness-of-fit plots and visual predictive check were performed. RESULTS One compartment model with first-order absorption was used to describe the in vivo behavior of carbamazepine. The final model parameters were as follows:CL=3.25×(WT/29.8)^0.22×e^0.05(AA=1)×e^ηCL(L·h^-1), V_d=34.78×e^ηVd(L), K_a=1.2·h^-1. Where AA=1 if CYP1A2-163 was AA, and AA=0 if CYP1A2-163 was CA or CC. The drug clearance nonlinearly increases as the epileptic children gain weight and the CYP1A2-163C>A mutation could accelerate the metabolism of carbamazepine. CONCLUSION The body weight and CYP1A2 polymorphisms were associated with the CL. It is recommended to consider the patient's weight and CYP1A2 genotype before taking carbamazepine.