卡马西平在东北地区癫痫患者中的群体药代动力学模型建立与剂量选择

Population pharmacokinetic model of carbamazepine and dosing strategies in epileptic patients of northeast China

目的根据癫痫患者卡马西平血药浓度,建立卡马西平群体药代动力学模型,为临床卡马西平个体化用药提供参考。方法收集2016年7月至2018年3月于我院进行常规监测卡马西平血药浓度的东北地区癫痫患者135例,共采集390个血药浓度作为建模依据。以年龄、性别、体重、服药日剂量、肝功能指标、合并用药等作为协变量,用一级吸收及消除的药代动力学模型,通过非线性混合效应模型(NONMEN)法建立癫痫患者卡马西平群体药代动力学模型并验证。用蒙特卡罗法根据群体药代动力学参数优化卡马西平给药剂量。结果剂量(TAMT)和合用丙戊酸钠(VPA)为卡马西平清除率(CL)的影响因素。最终模型为CL=0. 74×1. 50^(VPA)+(TAMT/473. 40)×1. 94 (合用丙戊酸VPA=1,否则VPA=0),合用丙戊酸的患者需要增加卡马西平给药剂量。结论卡马西平的清除率随剂量的增加以线性的方式增加,合并使用丙戊酸会增加卡马西平的清除率和剂量。所建模型稳定可靠,可用于临床卡马西平的个体化治疗。

Objective To establish the population pharmacokinetic model of carbamazepine in epileptic patients in northeast China according to its concentrations and provide references for individual medicine in clinical. Methods This study collected 135 epileptic patients of Northeast China treated with carbamazepine from Shengjing Hospital of China Medical University and 390 blood drug concentrations were used for a modeling basis. Covariates including age,sex,body weight,daily dose,liver function index,drug combination,etc,were investigated.The population pharmacokinetic model of carbamazepine was established using first-order absorption and elimination model by nonlinear mixed effect model( NONMEN) method. The final model was successfully verified. Monte Carlo simulations were performed to optimize dosage according population pharmacokinetic parameters of carbamazepine. Results Dosage( TAMT) and co-administration of valproate( VPA) were influencing factors of the clearance rate( CL) of carbamazepine. The final model formula was CL = 0. 74 × 1. 50 VPA+( TAMT/473. 40) × 1. 94,( concomitant with valproate,VPA = 1,otherwise VPA = 0). Dosage of carbamazepine should be increased when valproate was administrated.Conclusion There was a linear relationship between CL and dose ofcarbamazepine. The combined use of valproate could increase CL and dosage of carbamazepine. The established model was stable and reliable,which could be used for personalized therapy of carbamazepine.