外部验证支持下万古霉素群体药物动力学模型外推用于儿童患者模型引导的精准用药

Extrapolating the vancomycin population pharmacokinetic model for model-informed precision dosing in pediatric patients supported by external validation

目的本研究旨在对前期在皮肤软组织和骨关节感染的儿童患者中建立的万古霉素群体药物动力学模型进行外部验证,从而判断其是否可以外推至其他患者人群,用于指导万古霉素在儿童患者中的个体化应用。方法从医院信息系统中回顾性提取2021年6月—2022年12月入住我院儿童患者的年龄、性别、体重、实验室检查和万古霉素血药浓度等基本信息。将前期建立的儿童患者群体药物动力学模型在Phoenix软件中重建,通过贝叶斯法预测得到每个患者万古霉素的个体预测值,计算个体预测值与观测值的相对预测误差和均方根误差(百分比)等统计量和作图分析,对已建立的万古霉素群体药代动力学模型进行外部验证。结果共342例儿童患者的399个万古霉素稳态血药浓度数据用于最终的外部验证。除新生儿患者外,婴幼儿、儿童及青少年患者万古霉素血药浓度观测值及预测值计算获得平均预测误差和预测误差中位数均在±20%之内,均方根误差(百分比)在30%之内。根据感染类型分层,除新生儿患者外,呼吸系统感染、中枢神经系统感染及其他感染儿童患者万古霉素血药浓度观测值及预测值计算获得平均预测误差和预测误差中位数均在±20%之内,均方根误差(百分比)在30%之内(呼吸系统感染患者为31.1%)。结论前期建立的儿童患者万古霉素群体药物动力学模型可以外推至婴幼儿、儿童及青少年患者中用于模型引导的精准用药,从而指导万古霉素在儿童患者中的个体化应用。

Objective This study aimed to evaluate the predictive performance of the previously estimated vancomycin population pharmacokinetic(PopPK)model using data from pediatric populations with skin,soft tissue,and bone and joint infections,thus determining whether it can be extrapolated to other patient populations and guiding the individualized application of vancomycin in children.Methods The basic characteristics of pediatric patients,including age,gender,body weight,laboratory examination,and their blood concentrations of vancomycin from June 2021 to December 2022,were retrospectively extracted from the hospital information system.The pre-established population pharmacokinetic model of the pediatric patient group was reconstructed in the Phoenix software,and the individual predictive value of vancomycin for each patient was obtained through Bayes forecast,including the mean relative prediction error[MPE(%)],median relative prediction error[MDPE(%)],and root mean squared error(in percentage)(RMSE)for individual predictions,and external validation was carried out on the established pharmacokinetics model.Results A total of 399 vancomycin concentrations at steady state from 342 pediatric patients were included in thefinal external validation dataset.With the exception of newborns,based on observed and predicted values,the MPE(%)and MDPE(%)in infants,children and adolescents were within±20%,and the RMSE was within 30%.Based on the type of infection,the MPE(%)and MDPE(%)were within±20%and the RMSE was within 30%(31.1%in patients with respiratory infection)in pediatric patients with respiratory infection,central nervous system infection and other infections,excluding neonatal patients.Conclusion The previously established vancomycin PopPK model could be used in clinical practice in infants,children and adolescents to optimize vancomycin precise dosing,thereby guiding the individualized application of vancomycin in children.