基于不同群体药动学分析工具建立真实世界丙戊酸群体药代动力学模型

Real-world population pharmacokinetic models of valproic acid based on different population pharmacokinetic analysis tools

目的:基于NONMEM和MONOLIX 2种不同群体药动学分析工具建立真实世界丙戊酸群体药动学模型(PPK),探索可能影响丙戊酸血药浓度的潜在协变量,为癫痫患者使用丙戊酸提供科学依据。方法:回顾性收集2021年1月—2022年12月南京医科大学第二附属医院收治的167例癫痫患者239个丙戊酸稳态血药浓度数据资料,按随机数字表法将其分为模型组(n=111)与验证组(n=56)。2种群体药动学分析工具同时建立适合真实世界的群体药动学模型,采用拟合度优度诊断、可视化预测检验对所得的模型进行内部验证和外部验证,评估模型的预测能力。结果:该群体药动学为一室模型,在使用NONMEM软件建立的最终模型中纳入了联合用药(DDI)-美罗培南和给药方式(ROUTE)作为协变量;而在使用MONOLIX软件建立的最终模型中纳入了联合用药(DDI)-美罗培南和体质量(BW)作为协变量。与此同时,与NONMEM相比较,MONOLIX软件所得到的最终模型具有更好的精密度和准确度。结论:本研究初步构建了适用于癫痫患者给予丙戊酸剂量指导的群体药动学模型。

Objective To establish a real-world population pharmacokinetic model(PPK)of valproic acid(VPA)based on two different population pharmacokinetic analysis tools(NONMEM and MONOLIX),explore potential covariates that may affect the plasma concentration of valproic acid,and provide a scientific basis for the use of valproic acid in patients with epilepsy.Methods A total of 239 VPA steady-state plasma concentration data of 167 epileptic patients admitted to the Second Affiliated Hospital of Nanjing Medical University from January 2021 to December 2022 were retrospectively collected and divided into model group(n=111)and validation group(n=56)according to randomization method.Two population pharmacokinetic analysis tools were used to establish a population pharmacokinetic model suitable for the real world.The model was validated internally and externally by means of goodness-of-fit diagnosis and visual prediction test to evaluate the predictive ability of the model.Results The pharmacokinetics of the population was a one-chamber model.The final model established by NONMEM software included DDI-Meropenem and ROUTE as covariables.In the final model built using MONOLIX software,the combination drug(DDI)-meropenem and body weight(BW)were included as covariables.At the same time,compared with NONMEM,the final model obtained by MONOLIX software has better precision and accuracy.Conclusions In this study,a population pharmacokinetic model for valproic acid dose guidance in epileptic patients was established.