Zahir Hamim, McLachlan Andrew J, Nelson Ameeta, McCaughan Geof, Gleeson Margaret, Akhlaghi Fatemeh
Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, Rhode Island 02881, USA.
Ther Drug Monit. 2005 Aug;27(4):422-30. doi: 10.1097/01.ftd.0000170029.36573.a0.
The goal was to study the factors affecting tacrolimus apparent clearance (CL/F) in adult liver transplant recipients. Tacrolimus dose and concentration data (n = 694) were obtained from 67 liver transplant recipients (22 female and 45 male), and the data were analyzed using a nonlinear mixed-effect modeling (NONMEM) method. A 1-compartment pharmacokinetic model with first-order elimination, an absorption rate constant fixed at 4.5 hours, and first-order conditional estimation was used to describe tacrolimus disposition. The predictive performance of the final model was evaluated using data splitting and assessing bias and precision of the estimates. The population estimate of tacrolimus CL/F and apparent volume of distribution (V/F) were found to be 21.3 L/h (95% confidence interval, CI, 18.0-24.6 L/h) and 316.1 L (95% CI 133-495 L), respectively. Neither patient's age, weight, gender, nor markers of liver function influenced tacrolimus CL/F. The final model was TVCL = 21.3 + 9.8 x (1 - HEM) + 3.4 x (1 - ALB) - 2.1 x (1 - DIL) - 7.4 x (1 - FLU), where TVCL, typical estimate of apparent clearance, HEM = 0 if hematocrit <35%, otherwise 1; ALB = 0 if albumin <3.5 g/dL, otherwise 1; DIL = 0 if diltiazem is coadministered, otherwise 1; FLU = 0 if fluconazole is coadministered, otherwise 1. This study identified the factors that significantly affect tacrolimus disposition in adult liver transplant recipients during the early posttransplantation period. This information will be helpful to clinicians for dose individualization of tacrolimus in liver transplant recipients with different clinical conditions including anemia or hypoalbuminemia or in those patients receiving diltiazem or fluconazole.
本研究旨在探讨影响成年肝移植受者他克莫司表观清除率（CL/F）的因素。收集了67例肝移植受者（22例女性，45例男性）的他克莫司剂量和浓度数据（n = 694），并采用非线性混合效应建模（NONMEM）方法进行分析。采用具有一级消除的单室药代动力学模型，吸收速率常数固定为4.5小时，并采用一级条件估计来描述他克莫司的处置情况。通过数据拆分以及评估估计值的偏差和精度来评价最终模型的预测性能。结果发现，他克莫司CL/F和表观分布容积（V/F）的总体估计值分别为21.3 L/h（95%置信区间，CI，18.0 - 24.6 L/h）和316.1 L（95% CI 133 - 495 L）。患者的年龄、体重、性别以及肝功能指标均未影响他克莫司CL/F。最终模型为TVCL = 21.3 + 9.8 x (1 - HEM) + 3.4 x (1 - ALB) - 2.1 x (1 - DIL) - 7.4 x (FLU)，其中TVCL为表观清除率的典型估计值，若血细胞比容<35%，HEM = 0，否则HEM = 1；若白蛋白<3.5 g/dL，ALB = 0，否则ALB = 1；若同时给予地尔硫䓬，DIL = 0，否则DIL = 1；若同时给予氟康唑，FLU = 0，否则FLU = 1。本研究确定了在肝移植术后早期显著影响成年肝移植受者他克莫司处置的因素。这些信息将有助于临床医生对不同临床情况（包括贫血或低白蛋白血症）的肝移植受者，或接受地尔硫䓬或氟康唑治疗的患者进行他克莫司的剂量个体化调整。
