中国肾移植患者西罗莫司群体药动学模型研究

Population Pharmacokinetics of Sirolimus in Chinese Renal Transplantation Patients

回顾性收集60例中国肾移植患者常规监测的西罗莫司(1)稳态谷浓度(c0)及病理生理数据,检测患者CYP3A5*3基因型,采用非线性混合模型(NONMEM)软件建立中国肾移植患者服用1后的群体药动学(PPK)模型,并定量研究包括年龄、性别、体重、肝肾功能、CYP3A5*3基因型等因素对于PPK参数的影响。最终模型采用Bootstrap法验证。共回顾性收集患者移植后不同阶段的1血药浓度数据486个,平均c0浓度为(7.1±3.4)ng/ml。60位患者中包括3、22、35位CYP3A5*1/*1、*1/*3及*3/*3基因型。结果表明中国肾移植患者中1药动学符合一室模型,清除率(CL/F)为(13.1±0.78)L/h;分布容积(Vd/F)为(755±38.2)L;吸收速率常数(Ka)为2.20 h-1。体重、总胆红素(TBIL)和CYP3A5基因型对1的清除率均影响显著(P<0.01)。

The steady state trough concentration （co） of sirolimus （1） and pathophysiological data of 60 Chinese renal transplantation patients were enrolled retrospectively. The CYP3A5＊3 genotype of each patient was determined. The nonlinear mixed effect model （NONMEM） software was adopted to establish the population pharmacokinetic （PPK） model for 1 in Chinese renal transplantation patients. The influences of age, gender, body weight, renal and liver function and CYP3A5＊3 genotype on PPK parameters were quantitatively investigated. Bootstrap method was used for the validation of final model. Total 486 co data of 1 were obtained from 60 patients with different stages. The average value of Co was （7.1±3.4）ng/ml. There were 3, 22 and 35 patients with CYP3A5 ＊ 1/＊ 1, ＊ 1/＊3 and ＊3/＊3 genotype. The results showed that a one-compartment model was the most suitable model for Chinese renal transplantation patients. The clearance （CL/F）, volume of distribution （Vd/F） and absorption rate constant （Ks） were （13.1±0.78）L/h, （755± 38.2） L and 2.20 h-1, respectively. The body weight, total bilirubin （TBIL） and CYP3A5＊3 genotype were found to have significant influences on clearance of 1 （P〈0.01）.