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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 pharmacodynamic (PPD) model to investigate the dose-response relationship of elevated serum ammonia in patients with epilepsy induced by valproic acid (VPA) to promote safe medication. Methods: The published research data were extracted and searched. The plasma drug concentration of VPA was taken as the pharmacokinetic index and the blood ammonia concentration was taken as the pharmacodynamic index. The data were analyzed by nonlinear mixed effect modeling. Pharmacodynamic structural model selection Sigmoid-Emax model. The goodness of fit, bootstrap method and intuitionistic predictive test were used to verify the model’s predictive performance. External validation of the model with data not modeled. Results: The typical population of PPD model parameters were: E0 (baseline value) = 25.09μg · dL -1, EC50 (concentration of effect chamber at half maximal effect) = 107.26 mg · L -1 , γ (steepness factor) = 4.00, Emax (maximum effect parameter) = 471.95μg · dL -1. The internal and external verification results show that the final model is stable and the prediction result is reliable. Conclusion: This study successfully established a PPD model that can reflect the quantitative relationship between plasma concentration of valproic acid and blood ammonia level, which can provide a reference for clinical safe medication.