他克莫司在中国肾移植患者中的群体药物动力学研究

Population pharmacokinetics of tacrolimus in Chinese renal transplant patients

本研究旨在考察口服他克莫司(tacrolimus)在中国肾移植患者中的群体药物动力学特征并探讨群体药物动力学参数和相关因素间的关系。研究中回顾性搜集了58例肾移植患者的802份他克莫司稳态全血样本资料。患者随机分为模型建立组(41例)和模型验证组(17例)。用非线性混合效应模型(NONMEM)程序中的一级评估法(first-order estimation,FO)对模型建立组的数据进行分析。计算清除率(CL/F)、表观分布容积(V/F)的群体典型值,定量评价人口统计学指标、生化指标和合并用药等固定效应因素对药物动力学参数的影响。单室一级吸收和消除模型能够较好地拟合数据。最终模型包含了移植术后时间(POD)、红细胞压积(HCT)、谷草转氨酶(AST)、合并使用佩尔地平(NICA)和地尔硫(DIL)等对CL/F的影响。用模型验证组数据进行验证的结果表明观测值和模型预测值之间没有明显的偏倚,模型的稳定性和准确度较好。CL/F和V/F的群体典型值分别为21.7 L.h-1和241 L;相应的个体间变异分别为41.6%和49.7%。观测值与预测值之间的残差SD为2.19μg.L-1。本文建立的模型可以为临床他克莫司剂量选择提供一定参考。

The goal of this study is to investigate the population pharmacokinetics of oral tacrolimus in Chinese renal transplant patients and to identify possible relationship between covariates and population parameters. Details of drug dosage history, sampling time and concentration of 802 data points in 58 patients were collected retrospectively. Before analysis, the 58 patients were randomly allocated to either the model building group （ n = 41 ） or the validation group （ n = 17 ）. Population pharmacokinetic data analysis was performed using the nonlinear mixed-effects model （NONMEM） program on the model building group. The pharmacokinetics of tacrolimus was best described by a one compartment model with first-order absorption and elimination. Typical values of apparent clearance （CL/F）, apparent volume of distribution （V/F） were estimated. A number of covariates including demographic index, clinical index and coadministration of other drugs were evaluated statistically for their influence on these parameters. The final population model related clearance with POD （post operative days ）, HCT （haematocrit）, AST （aspartate aminotransferase） and coadministration of nicardipine and dihiazem. Predictive performance of the final model evaluated with the validation group showed insignificant bias between observed and model predicted concentrations. Typical value of CI/F and V/F was 21.7 L · h^-1 and 241 L, inter-patient variability （RSD） in CI/F and V/F was 41.6% and 49.7% , respectively. The residual variability （SD） between observed and model-predicted concentrations was 2. 19 μg · L^-1. The population pharmacokinetic model of tacrolimus in Chinese renal transplant patients was established and significant covariates on the tacrolimus model were identified.