肾移植患者麦考酚酸的群体药动学研究

Population Pharmacokinetics of Mycophenolic Acid in Chinese Adult Renal Transplant Patients

目的建立国人肾移植患者在移植初期3个月的群体药动学模型。方法研究对象为52例采用环孢素、吗替麦考酚酯(MMF)和糖皮质激素三联免疫抑制治疗方案的肾移植患者。收集其服药后不同时相的血样560份以及相应的生理、病理和实验室检查数据。运用非线性混合效应模型建立麦考酚酸的群体药动学模型,考察身高、体重、年龄、性别、剂量、血清肌酐、移植术后天数、合并用药、UGT1A9启动子11个单核苷酸基因多态性等对药动学参数的影响。模型验证采用200次bootstrap。结果以一级吸收和消除的二房室模型拟合麦考酚酸的药动学过程为佳,一级速率条件算法计算。体重和移植术后时间是麦考酚酸清除率的影响因素。麦考酚酸清除率的群体药动学公式为:CL/F(L.h-1)=0.554.TBW(kg).(1-e-1.14.POD)。MPA平均清除率为31 L.h-1,与白种人的文献报道值相吻合。Bootstrap法的验证结果与模型计算值也相符。结论建立的麦考酚酸群体药动学模型有一定代表性,为采用Bayesian法进行个体化给药奠定基础。

OBJECTIVE To characterize the population pharmacokinetics （PK） of mycophenolic acid （MPA） in Chinese adult renal transplant patients during the first three months after transplantation. METHODS Fifty-two Adult renal transplant recipients, who were orally administered with mycophenolate mofetil, cyclosporine and corticosteroids, were enrolled in this study. Totally 560 blood samples were collected from their MPA PK profiles with relating demographical, pathological and laboratory test results. Nonlinear mixed effect modeling was employed to establish the population PK model of MPA. Age, gender, height, weight, dose, serum creatinine, co-administraed drugs, post-operation day and 11 single nucleotide polymorphisms in UGT1A9 promoter area ere, were screened as covariates. The final PK model was validated using 200 bootstrap techniques. RESULTS A two-compartment model with first-order absorption and elimination provided the best fitting. First order conditional estimation was employed as the algorithm. Total body weight and time after transplantation were identified as covariates influencing the clearance of MPA. The final population PK model for MPA was listed below： CL/F（ L · h^-1 ） = 0. 554 · TBW （kg） · （1 -e^-1 14. POD）. The final population model yielded mean population CL/F value of 31 L · h^ -1, which was consistent with those of previous reports conducted in Caucasians. Bootstrapped results showed close agreement between pairs of bootstrapped and final model parameter estimates. CONCLUSION It is the first time that population PK parameters for MPA are determined in Chinese renal transplant recipients. These can be used to achieve specific target MPA concentrations or areas under the concentration-time curve with the Bayesian methods.