基于非线性混合效应模型法建立的拉莫三嗪群体药动学模型研究进展

Research Progress of Population Pharmacokinetic Model of Lamotrigine Based on Nonlinear Mixed Effect Model

目的探讨拉莫三嗪在不同群体中的群体药动学特征及其影响因素,为建立更精准的群体药动学模型提供参考。方法系统检索PubMed、Embase、Web of Science、Science Direct及Cochrane Library数据库中采用非线性混合效应模型(NONMEM)法在人体内进行的拉莫三嗪群体药动学的研究,时间为1995年1月—2021年7月。结果共纳入研究20项,其中17项研究将拉莫三嗪的药动学特征描述为一室模型结构。伴随抗癫痫药物、体质量和基因多态性被认为是影响拉莫三嗪清除的3个最常见显著协变量,其他显著协变量研究较少。结论在建立新的拉莫三嗪群体药动学模型时,应考虑合用其他抗癫痫药物、体质量、基因型等重要协变量因素;对于妊娠妇女等特殊人群,应纳入特殊人群的生理病理特征作为协变量因素,同时进行内部验证和外部验证增加模型的普适性。

Objective To summarize the population pharmacokinetic characteristics and influencing factors of lamotrigine(LTG)in different age groups,and to provide a reference basis for the establishment of a more accurate population pharmacokinetic model in the future.Methods Five databases including PubMed,Embase,Web of Science,Cochrane Library,and Science Direct were systematically searched from January 1995 to July 2021.Population pharmacokinetic studies of LTG conducted in human using a nonlinear-mixed effect model(NONMEM)approach were included for a systematic review.Results A total of 20 studies were included in this review.In most studies,the pharmacokinetics of LTG was described as an one-compartment model.The three most common significant covariates that affect LTG clearance include concomitant antiepileptic drugs,body weight and gene polymorphism.There are a few studies on other significant covariates.Conclusion When establishing a new population pharmacokinetic model of LTG,important covariates such as the use of other antiepileptic drugs,body weight and genotypes should be considered.For pregnant women and other special groups,the physiological and pathological characteristics of the special population should be included as covariates to establish the population pharmacokinetic model of the special population.At the same time,internal and external verification should be carried out to increase the universality of the model.