肾移植患者西罗莫司的群体药动学研究

目的:建立中国肾移植患者西罗莫司的群体药动学模型,为实施个体化用药提供理论支持。方法:选择47名肾移植术后采用西罗莫司+泼尼松+环孢素或他克莫司或霉酚酸酯(MMF)三联免疫抑制治疗的患者为研究对象,回顾性收集47名患者服药后的101个西罗莫司稳态血药浓度及相应的试验室检查数据,运用Winnonmix药动学软件,采用非线性混合效应模型(NONMEM)分析体重、年龄、性别、给药剂量、合并用药、肌酐清除率等对药动学参数的影响。最终模型的验证采用Jackknife法进行内部验证。结果:西罗莫司符合无滞后时间的一级消除动力学一室模型。固定效应结果量子,合用MMF和体重可影响药物清除率。最终模型公式为:CL/F(L·h-1)=11.01×0.14MMF+0.089×W。CL/F和Vd/F的群体典型值分别是11.01L·h-1和3616L,个体间变异分别为62.82%和85.07%。观测值和预测值间的残差(SD)和相关系数(r)分别是1.0ng·mL-1和0.94。结论:所建立的群体药动学模型能较好地估算服用西罗莫司的肾移植患者的个体及群体药动学参数,对指导临床个体化用药具有重要意义。

Study on Population Pharmacokinetics of Sirolimus in Renal Transplantation Patients

OBJECTIVE: To establish the population pharmacokinetics (PK) model of sirolimus in Chinese renal transplantation patients, and to provide theory support for personalized drug use. METHODS: 47 renal transplantation patients, who were orally administrated with sirolimus+prednisone+ciclosporin or tacrolimus or mycophenolate mofetil (MMF) after transplantation, were enrolled in this study. Total 101 steady-state trough blood concentrations of sirolimus and related laboratory test results were retrospectively collected. Effects of weight, age, gender, drug dose, drug combination, creatinine clearance rate. on pharmacokinetic parameter were analyzed by NONMEM. Jackknife method was used for the validation of final model. RESULTS: A one-compartment model with first-order elimination pharmacokinetics without lag time provided the best fitting. In all fixed effects,combined use of MMF and weight influenced the clearance of sirolimus. The final population PK model for sirolimus was listed below:CL/F(L·h-1)=11.01×0.14MMF+0.089×W. Typical value of CL/F and Vd/F was 11.01 L·h-1 and 3 616 L, inter-patient variability in CL/F and Vd/F was 62.82% and 85.07%, respectively. The residual variability (SD) and relationship coefficient (r) between observed value and model-predicted value was 1.0 ng·mL-1 and 0.94. respectively. CONCLUSION: The established model could estimate individual and population pharmacokinetic parameters of renal transplantation patients, and it is of great significance for the personalized drug use.