基于NONMEM法建立紫杉醇群体药动学模型  

Establishment of population pharmacokinetic model of paclitaxel based NONMEM method

作　　者：陈权耀 黄品芳[1] 林翠鸿[1] 刘亦伟[1] 林玮玮[1] 翁秀华[1] 林荣芳[1] 王长连[1] 

机构地区：[1]福建医科大学附属第一医院,福建福州350005 [2]厦门市妇幼保健院药学部,福建厦门361003

出　　处：《中国医院药学杂志》2017年第18期1831-1835,共5页Chinese Journal of Hospital Pharmacy

基　　金：福建省卫生系统中青年骨干人才培养计划重点项目(编号:2014-ZQN-ZD-15);教育部留学回国人员第46批科研启动基金(编号:2013B019)

摘　　要：目的:建立国人紫杉醇(paclitaxel,PTX)群体药动学(population pharmacokinetic,PPK)模型,为制定个体化给药方案提供理论支持。方法:收集138例接受紫杉醇治疗的肿瘤患者(建模组105例,验证组33例)210个血样,HPLC法测定紫杉醇血药浓度,PCR-RFLP法检测MDR1 C3435T。应用非线性混合效应模型(NONMEM)法,考察MDR1 C3435T基因多态性、合并用药及病理生理因素对紫杉醇药动学参数的影响,建立紫杉醇PPK模型。对模型进行拟合优度诊断、自举法(Bootstrap)内部验证,正态预测分布误差法(NPDE)及外部验证考察模型预测能力。结果:紫杉醇清除率(CL)和表观分布容积(Vd)的群体典型值分别为64.7 L·h^(-1)和1 240 L,患者内生肌酐清除率(CLcr)和给药速率(RATE)显著影响紫杉醇清除率。最终模型Bootstrap法验证结果与模型计算值相符,拟合优度、准确度及精密度均优于最简模型。结论:紫杉醇PPK最终模型稳定、有效,可结合Bayesian反馈法为临床优化给药方案提供科学依据。OBJECTIVE To establish a population pharmacokinetic（PPK）model of paclitaxel（PTX）in Chinese people,and provide theoretic supports for personalized medication.METHODS Totally 138 patients were divided into model group（n=105）and valid group（n=33）.HPLC method was used to determine plasma concentrations of paclitaxel in210 samples.PCRRFLP technique was used to genotype the MDR1 C3435 T.The effects of MDR1 C3435 T polymorphisms,other medication,physiological and pathological factors on pharmacokinetic parameters were investigated by nonlinear mixed effects model（NONMEM）to establish PPK model of paclitaxel.Goodness of fit diagnosis was applied to final PPK model and internal validity of the model was evaluated by Bootstrap.Normalized predictive distribution error（NPDE）and external validation were adopted to evaluate the predictive ability and reliability.RESULTS Estimated values for clearance and volume of distribution were 64.7 L h^-1 and 1 240 L.The clearance was significantly associated with creatinine clearance and medication rate.CONCLUSION The final model is stable and effective,may provide a scientific basis for using Bayesian feedback to optimized medication.

关 键 词：紫杉醇 群体药动学 非线性混合效应模型 基因多态性 

分 类 号：R969.1[医药卫生—药理学]