薛 领 芮建中 张 彦 缪丽燕. 造血干细胞移植患者他克莫司的群体药动学研究J. 药学学报, 2009,44(10): 1145-1151.
引用本文: 薛 领 芮建中 张 彦 缪丽燕. 造血干细胞移植患者他克莫司的群体药动学研究J. 药学学报, 2009,44(10): 1145-1151.
XUE Ling, Rui-Jian-Zhong, Zhang- Pan, Jiu-Li-Yan. Population pharmacokinetic study of tacrolimus in patients with hematopoietic stem cell transplantJ. 药学学报, 2009,44(10): 1145-1151.
Citation: XUE Ling, Rui-Jian-Zhong, Zhang- Pan, Jiu-Li-Yan. Population pharmacokinetic study of tacrolimus in patients with hematopoietic stem cell transplantJ. 药学学报, 2009,44(10): 1145-1151.

造血干细胞移植患者他克莫司的群体药动学研究

Population pharmacokinetic study of tacrolimus in patients with hematopoietic stem cell transplant

  • 摘要:

    本研究建立了造血干细胞移植患者他克莫司的群体药动学 (population pharmacokinetics, PPK) 模型, 估算其群体药动学参数, 为造血干细胞移植患者他克莫司的个体化给药提供参考。 研究过程中, 回顾性收集了68例造血干细胞移植患者671份常规监测的血药浓度数据, NONMEM软件的一级估算法 (first-order estimation, FO) 对数据进行分析, 用自举法和数据分割法对模型稳定性和可信度进行验证。基本模型选择一级吸收和一级消除的单室模型, 定量考察了人口学特征、血生化和血常规指标、合用药物, 及原发疾病、术后时间、移植类型、供体来源等因素对药动学参数的影响, 同时对药动学参数的周期间变异 (inter-occasion variability, IOV) 也进行了考察。他克莫司清除率 (CL)、分布容积 (V)、绝对生物利用度 (F) 的群体典型值分别为12.1 L·h−1686 L42.2%, 这些参数的个体间变异分别为23.5%96.4%43.8%, 浓度观测值与预测值之间的残余误差为3.03 ng·mL−1; 研究发现, 肝药酶抑制剂 (INHI)、术后时间 (POD)、年龄 (AGE) 对清除率 (CL) 有显著影响, 血红蛋白 (HGB) 浓度对分布容积 (V) 有显著影响; CLVFIOV分别为22.2%6.23% 30.3%本研究结果对他克莫司在造血干细胞移植患者中实现个体化给药具有重要应用价值。

     

    Abstract:

    The present study is to establish the population pharmacokinetic (PPK) model of tacrolimus   and to estimate PPK parameters of tacrolimus for the individualization of tacrolimus administration in patients with hematopoietic stem cell transplant.  A total of 671 blood samples were collected from 68 hematopoietic stem cell transplant patients and clinical data were retrospectively collected from the medical records of these  patients.  Population pharmacokinetical analysis was performed using the nonlinear mixed-effect model (NONMEM) program.  The Bootstrap and data splitting were used simultaneously to validate the final population pharmacokinetical models.  The basic structural model was best described as one-compartment pharmacokinetical model with first-order absorption and elimination.  A number of covariates including demographic characteristic, biochemical and hematological index, combined drugs, inter-occasion variability (IOV) and other variables, e.g. primary disease, post operation days (POD), the type of transplantation and the sources of donor, were screened for their influence on the pharmacokinetic parameters of tacrolimus.  The population typical values of      tacrolimus CL, V, F were 12.1 L·h−1, 686 L, 42.2%; and the inter-individual variability of these parameters were 23.5%, 96.4%, 43.8%, respectively.  The absorption rate constant was fixed 4.3 h−1.  The residual error     between observed and model- predicted concentration was 3.03 ng·mL−1.  The CYP enzyme inhibitor (INHI), POD and age were identified to be the main covariates that influence tacrolimus CL, and hemoglobulin (HGB) was the main covariate that may explain the variability in tacrolimus V.  The IOV of CL, V, F were 22.2%, 6.23%, 30.3%, respectively.  The population pharmacokinetic data obtained in the present study have significant clinical value for the individualization of tacrolimus therapy in hematopoietic stem cell transplant patients.

     

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