中国癫痫儿童左乙拉西坦群体药代动力学模型探讨

Population pharmacokinetic analysis of levetiracetam in Chinese children with epilepsy.

目的建立中国癫痫儿童左乙拉西坦(LEV)群体药代动力学(PPK)模型,指导临床合理用药。方法分析2009年6月至2010年12月北京大学第一医院小儿神经门诊及病房收集的220例服用LEV癫痫患儿的250个LEV血药浓度数据,使用非线性混合效应模型(NONMEM)软件,按照一室一级吸收和消除模型,建立我国癫痫患儿LEV的PPK模型。使用正态化预测分布误差(NPDE)方法验证模型。结果 LEVPPK基础模型:清除率(CL/F)=1.56×EXP[ETA(1)]L/h,表观分布容积(V/F)被固定为20L,吸收速率常数(KA)=EXP[ETA(3)]/h;最终模型:CL/F=[1.35×(体重/25.26)0.578]L/h,V/F=20L,KA=2.11×EXP[ETA(3)]/h;CL/F、V/F和KA群体值分别为1.35L/h、20L和2.11/h。经过NPDE方法验证,所建立的最终模型有良好稳定性和预测效能。结论本文建立了中国癫痫患儿LEVPPK模型,模型通过验证及预测效能,可用于指导临床用药。体重是对清除率影响最明显的协变量。

Objective To establish a population pharmacokinetic（PPK）model of levetiraeetam in Chinese children with epilepsy.Methods A total of 250 data from 220 epileptic children were analyzed.Levetiracetam concentrations were de- termined by the HPLC method.PPK model of levetiracetam was established using NONMEM, a population pharmacoki- netic computer program, according to one-compartment model with first-order absorption and elimination.To validate a model, the normalized prediction distribution errors （NPDE） method was used.Results Regression equation of the base model of levetiraeetam was obtained, ie, clearance （CL/F） = 1.56×EXP [ ETA （ 1 ） ], volume of distribution （V/F） was fixed 20, and Ka = EXP [ ETA （3） ], and that of the final model was as follows： CL/F （L/h） = 1.35×（WEIGHT/25.26）^0.578, V/F （L） =20, KA （/h） =2.11× EXP [ ETA （ 3 ） ] .The final PPK model was demonstrated to be stable and effective in the predic- tion of serum levetiraeetam concentrations by NPDE.Conclusion A one-compartment mixture model with first-order absorption adequately describes the levetiracetam concentrations.Weight is identified as a significant eovariate on leveti- racetam clearance in this study.