肾移植患者西罗莫司的群体药代动力学模型研究

Study on population pharmacokinetics model of sirolimus in renal transplantation patients

目的 :建立肾移植患者口服西罗莫司片的群体药代动力学模型,研究西罗莫司在人体内的药动学特点,为实施个体化用药提供理论支持。方法:以111例肾移植术后采用西罗莫司进行免疫抑制治疗的患者为研究对象,回顾性收集患者常规监测的西罗莫司稳态血药浓度及相应的实验室检查数据,运用Phoenix NLME药动学软件建立西罗莫司的群体药动学模型,分析影响药动学参数的因素。最终模型采用Bootstrap法和可视化预测检查进行内部验证。结果:西罗莫司符合一级消除动力学一室模型。发现红细胞比容对清除率有影响,碱性磷酸酶对分布容积有影响,获得的最终模型CL/F值为10.8 L/h,V/F为1 011 L。Bootstrap验证和可视化预测检查的评价结果表明模型预测结果可靠。结论 :本研究成功建立了肾移植患者西罗莫司的群体药动学模型,考察了年龄、体重、性别、合并用药以及各生化指标对模型的影响,为实现西罗莫司的临床合理用药提供参考。

Objective： To construct a population pharmacokinetics （PPK） model of sirolimus in Chinese renal transplantation patients,study the pharmacological characteristics of sirolimus,and provide theory support for personalized drug use.Methods： One hundred and eleven renal transplantation patients,who were orally administrated with sirolimus after transplantation,were enrolled in the study.Steady-state concentrations of sirolimus and related laboratory test results were retrospectively collected.Phoenix NLME was used to perform a population pharmacokinetics model.Influence factors on pharmacokinetic parameter were analyzed.Performance of final model was internally assessed by bootstrapping and visual predictive checking （VPC）.Results：A one-compartment model with first-order elimination pharmacokinetics provided the best fitting.In all fixed effects,hematocrit influenced the clearance of sirolimus,alkaline phosphatase influenced volume of distribution.Typical value of CL/F was 10.8 L/h,typical value of V/F was 1011 L.Stability and predictive performance were accepted by bootstrapping and VPC.Conclusion： A PPK model of sirolimus in Chinese renal transplantation patients is successfully established in this study.Effects of weight,age,gender,drug dose,drug combination,liver and kidney function on pharmacokinetic parameter were inspected.It is of great significance for clinical rational drug use of sirolimus.