摘要
目的用非线性混合效应模型(NONMEM)方法建立左乙拉西坦(LEV)在中国癫痫患儿中的群体药代动力学模型。方法回顾性收集298例口服左乙拉西坦癫痫患儿(6月~16岁)的318份血药浓度数据及相关信息。用NONMEM及辅助软件建立癫痫患儿的群体药代动力学模型,并考察人口学信息、肾小球滤过率估计值(e GFR)、合并用药等固定效应对药代动力学参数的影响。最终模型用拟合优度(GOF)、自举法(Bootstrap)进行内部验证以及正态化预测分布误差(NPDE)评估模型参数的精确度。结果最终模型CL/F的群体典型值为4. 31L·h^-1,将V/F固定为20 L。其中体重、LEV每日给药剂量以及肾小球滤过率对CL/F的影响较大。结论用NONMEM法初步建立了服用左乙拉西坦癫痫患儿的群体药代动力学模型,经验证稳定可靠,可用于预测血药浓度,为临床指导用药提供参考。
Objective To establish the population pharmacokinetics model of levetiracetam( LEV) in epileptic children using a nonlinear mixed effects modeling( NONMEM) approach. Methods A total of 318 samples and relevant information were collected from 298 epileptic children retrospectively,who were taken levetiracetam orally( age from 6 month to 16 years). The population pharmacokinetics model of the epileptic children was established by NONMEM method and auxiliary software,and the effects of fixed model such as demographic information,glomerular filtration rate( eGFR) and drug combination on pharmacokinetics parameters were investigated. The final model was validated by the GOF plots,bootstrap method and evaluated the accuracy of the model parameters by normalized prediction distribution errors( NPDE). Results The typical values of CL/F was 4. 31 L·h^-1 of the final model,V/F was fixed to 20 L. Body weight,LEV daily dose,and glomerular filtration rate have the large impact on CL/F. Conclusion This study preliminarily established population pharmacokinetics( PPK) model of LEV in the epileptic children by NONMEM. It has been verified to be stable and reliable,which can predict LEV concentrations. And this model can offer reference for clinical medication.
作者
申红爽
路童
徐善森
王环鑫
赵明明
肇丽梅
SHEN Hong-shuang;LU Tong;XU Shan-sen;WANG Huan-xin;ZHAO Ming-ming;ZHAO Li-mei(Department of Pharmacy,Shengjing Hospital of China Medical University, Shenyang 110004, Liaoning Province, China;School of Life Science and Biopharmaceutics, Shenyang Pharmaceutical University, Shenyang 110016,Liaoning Province,China)
出处
《中国临床药理学杂志》
CAS
CSCD
北大核心
2019年第14期1485-1488,1492,共5页
The Chinese Journal of Clinical Pharmacology
基金
国家自然科学基金青年基金资助项目(81703628)
