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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 establish a population pharmacokinetic model of kidney transplant recipients in China at the early stage of transplantation. METHODS: Fifty-two patients undergoing renal transplantation with cyclosporine, mycophenolate mofetil (MMF) and glucocorticoid triple immunosuppressive regimens were enrolled. 560 samples of blood samples collected at different phases after their administration were collected, and the corresponding physiological, pathological and laboratory data were collected. The population pharmacokinetic model of mycophenolic acid was established by nonlinear mixed effect model. The height, weight, age, sex, dosage, serum creatinine, days after transplantation, combined medication, 11 single nucleotide polymorphisms of UGT1A9 promoter Polymorphism and other pharmacokinetic parameters. Model verification using 200 bootstrap. Results The two-compartment model of first-order absorption and elimination of mycophenolic acid was better than that of the first-order rate condition. Body weight and time after transplantation were the influencing factors of mycophenolic acid clearance. The population pharmacokinetic formula for mycophenolic acid clearance was CL / F (L.h-1) = 0.554.TBW (kg). (1-e-1.14.POD). The average clearance rate of MPA was 31 L · h-1, which was consistent with the reported value in white man. Bootstrap method validation results and model calculations are also consistent. Conclusions The established model of mycophenolic acid group pharmacokinetics has certain representativeness and lays the foundation for individualized administration by Bayesian method.