中国癫痫患儿游离丙戊酸群体药动学模型的建立及应用

Development and application of population pharmacokinetic model of free valproic acid in pediatric epilepsy patients in China

目的建立丙戊酸(VPA)游离药物在癫痫患儿的群体药代动力学(popPK)模型,为指导癫痫患儿个体化应用VPA提供参考。方法收集中国医科大学附属盛京医院进行VPA血药浓度监测的癫痫患儿血样,利用UPLC-MS/MS检测VPA游离药物浓度。同时收集患儿的人口学信息、生化指标、用药情况等资料,将其作为协变量,考察其对游离VPA药代动力学参数的影响。建模采用一级吸收及消除的药代动力学模型,通过非线性混合效应模型(NONMEM)法建立中国癫痫患儿游离VPA popPK模型并进行验证。参考游离VPA的治疗窗,利用已建立的模型,在不同年龄体重患儿中模拟不同给药剂量下游离药物谷浓度的情况。结果本研究共纳入455例癫痫患儿,收集632个VPA血药浓度数据。通过逐步法,最后筛选出体重、年龄、日剂量为影响游离VPA CL/F的显著协变量,具体公式为CL/F=1.5×(BW/22)^(0.319)×(AGE^(1.24)/AGE^(1.24)+0.322^(1.24))×(DOSE/400)^(0.243),且模型经过验证较为稳定,并参考游离VPA的治疗窗,将模型应用于不同年龄及体重患儿的剂量优化调整。结论本研究所建立的中国癫痫患儿游离VPA群体药动学模型稳定可靠,可为指导VPA的临床个体化用药提供依据。

Objective To establish a population pharmacokinetic(popPK)model of free valproic acid(VPA)and provide reference for clinical guidance of individualized application of VPA in epileptic children.Methods Blood samples were collected from epileptic children who underwent routine therapeutic drug monitoring of VPA plasma concentration in Shengjing Hospital of China Medical University,and free drug concentrations were measured by UPLC-MS/MS.Demographic information,biochemical data,co-medication and others were also collected as covariates to investigate their effects on free VPA pharmacokinetic parameters.A first-order absorption and elimination pharmacokinetic model was used to establish and validate the free VPA popPK model in Chinese children with epilepsy by nonlinear mixed effects modeling(NONMEM).Referring to the therapeutic window of free VPA,the established model was used to simulate the trough free drug concentration at different doses in children at different ages and weights.Results A total of 455 children with epilepsy were enrolled in this study,and 632 VPA plasma concentration data were collected.In a stepwise approach,weight,age,and daily dose were finally included as significant covariates affecting CL/F of free VPA,and the specific formula was CL/F=1.5×(BW/22)^(0.319)×(AGE^(1.24)/AGE^(1.24)+0.322^(1.24))×(DOSE/400)^(0.243),and the model was validated to be robust.According to the therapeutic window of free VPA,the model was applied to dose optimization adjustment in children at different ages and weights.Conclusion The population pharmacokinetic model of free VPA in Chinese children with epilepsy is stable and reliable,which can provide basis for guiding the clinical individualized medication of VPA.