丙戊酸致癫痫患者血氨升高的群体药效学分析  

Population pharmacodynamics of hyperammonemia in epilepsy patients under valproic acid therapy

作　　者：汪洋[1] 刘茂昌[1] 李思婵 陈渝军[1] 张华年[1] 徐华[1] 万雄飞 WANG Yang LIU Mao-chang LI Si-chan CHEN Yu-jun ZHANG Hua-nian XU Hua WAN Xiong-fei(Wuhan Medical ＆ Healthcare Center for Women and Children, Hubei Wuhan 430016, China Second Worker＇s Hospital of Wuhan Tron and Steel Company, Hubei Wuhan 430085, China)

机构地区：[1]武汉市妇女儿童医疗保健中心,湖北武汉430016 [2]武钢第二职工医院,湖北武汉430085

出　　处：《中国医院药学杂志》2017年第8期754-757,共4页Chinese Journal of Hospital Pharmacy

基　　金：2016年度武汉市卫生计生科研基金资助项目(编号:WX16B18)

摘　　要：目的:建立群体药效学(PPD)模型考察丙戊酸(VPA)致癫痫患者血氨升高的量-效关系,以促进安全用药。方法:搜索提取已发表的研究资料,以患者VPA血浆药物浓度作为药动学指标,血氨浓度作为药效学指标,采用非线性混合效应建模进行数据分析。药效学结构模型选用Sigmoid-Emax模型。用拟合优度、自举法和直观预测检验对模型的预测性能进行内部验证。用未参与建模的数据对模型进行外部验证。结果:PPD模型参数的群体典型值分别为:E0(基线效应值)=25.09μg·dL^(-1),EC50(达最大效应一半时效应室浓度)=107.26 mg·L^(-1),γ(陡度因子)=4.00,Emax(最大效应参数)=471.95μg·dL^(-1)。内部验证和外部验证结果表明最终模型稳定,预测结果可靠。结论:本研究成功建立了能够反映患者丙戊酸血药浓度与血氨水平之间定量关系的PPD模型,可为临床安全用药提供参考。OBJECTIVE To establish a population pharmacodynamics（PPD）model to study the exposure-response relationship of valproic acid（VPA）and hyperammonemia,and to facilitate the medication safety.METHODS Data about hyperammonemia associated with VPA therapy were searched and extracted from the published literatures.The plasma concentration of VPA and plasma ammonia level were selected as the pharmacokinetic and pharmacodynamic parameters,respectively.A nonlinear mixed-effect population modelling approach was adopted for data analysis.A sigmoid Emax model for pharmacodynamic analysis was selected as the structural model.The predictive performance of the model was internally evaluated by goodness-of-fit,Bootstrapping and visual predictive check（VPC）.External confirmation was performed with data not enrolled for modeling.RESULTS The typical population values of pharmacodynamic parameters estimated in the model were as follows：E0（baseline effect）=25.09μg·dL^-1,EC50（the effect compartment concentration resulting in 50% of maximum effect）=107.26 mg·L^-1,γ（sigmoidicity factor）=4.00,Emax（maximum drug effect）=471.95μg·dL^-1.The stability and predictive performance of the model were acceptable in internal and external evaluations.CONCLUSION A PPD model is successfully established in this study to evaluate the quantitative relationship between plasma VPA concentrations and ammonia levels of patiens,which is helpful for optimizing the medication safety and rationality.

关 键 词：丙戊酸 血氨 高氨血症 不良反应 群体药效学 

分 类 号：R971.6[医药卫生—药品]