基于NONMEM法建立重症患者亚胺培南群体药动学模型  

Population pharmacokinetics of imipenem in critically ill patients based on nonlinear mixed effect model

作　　者：罗雪梅[1] 金路[1] 梁培[1] 葛卫红[1] LUO Xue-mei;JIN Lu;LIANG Pei;GE Wei-hong(Department of Pharmacy,the Affiliated Drum Tower Hospital of Nanjing University Medical School,Nanjing 210008)

机构地区：[1]南京大学医学院附属鼓楼医院药学部,南京210008

出　　处：《中南药学》2022年第2期452-455,共4页Central South Pharmacy

基　　金：南京药学会——常州四药医院药学科研基金资助项目(No.2019YX007)。

摘　　要：目的基于非线性混合效应模型法(NONMEM)软件建立亚胺培南群体药动学模型,用于重症感染患者的临床用药方案支持。方法收集2018年6月—2019年6月本院重症监护室病房中给予亚胺培南西司他丁治疗的144名患者(模型组95名,验证组49名)的临床资料,采用NONMEM法估算亚胺培南的群体药动学参数,建立群体药动学模型。将建好的模型完成拟合优度诊断、自举法内部验证及外部验证考察模型预测能力,完成模型验证。并就不同给药情况进行蒙特卡洛模拟,计算达标率。结果最终群体药动学模型为二室模型,各参数的典型值分别为CL 8.95 L·h^(-1),Q 1.82 L·h^(-1),V_(1)24.7 L,V_(2)30.5 L,患者内生肌酐清除率和性别显著影响亚胺培南清除率。当肾功能减退时可以减半剂量,而女性患者MIC>1 mg·L^(-1)时,可能需要联合用药。结论该群体药动学模型可以用于重症患者的亚胺培南给药剂量的指导。Objective To establish a population pharmacokinetic(PPK)model for imipenem in critically ill patients for individualized medication by nonlinear mixed effect model(NONMEM).Methods The clinical data of 144 ICU patients(95 in the model group,49 in the valid group)from June 2018 to June 2019 were collected,and the PPK model of imipenem was determined by NONMEM.The internal validity of the model was evaluated by Goodness of fit diagnosis and Bootstrap.The external validation was used to evaluate the predicaility and reliability.Monte Carlo simulations were conducted to estimate the probability of target attainment.Results NONMEM demonstrated that the data fit the two-compartment model.Typical population estimates of CL,Q,V_(1) and V_(2) were 8.95 L·h^(-1),1.82 L·h^(-1),24.7 L and 30.5 L,respectively.CLcr and gender might affect the clearance rate of imipenem.Dose should be halved in renal dysfunction and female patients might need combination therapy when MIC>1 mg·L^(-1).Conclusion The population pharmacokinetic model is valid and useful for the use of imipenem in critically ill patients.

关 键 词：非线性混合效应模型法 亚胺培南 群体药动学模型 重症患者 血药浓度 

分 类 号：R96[医药卫生—药理学]