Population Pharmacokinetics of Tacrolimus in Transplant Recipients: What Did We Learn About Sources of Interindividual Variabilities?
Population Pharmacokinetics of Tacrolimus in Transplant Recipients: What Did We Learn About Sources of Interindividual Variabilities?
复制标题
DOI：
10.1002/jcph.1325
复制
发表时间：
2019-03
影响因子：
2.9
通讯作者：
Tornatore KM
中科院分区：
文献类型：
--
作者：
Campagne O;Mager DE;Tornatore KM
他克莫司是一种钙调神经磷酸酶抑制剂，是器官移植后常用的免疫抑制剂，具有显著的患者间和患者内药代动力学变异性。在过去的20年里，使用群体药代动力学模型研究了变异性的来源。这篇文章提供了关于移植受者中他克莫司的非线性混合效应分析的最新进展。其目的是建立对当前数据的详细概述，并调查由模型确定的协变量关系。对63篇已发表的分析进行了综述，并提取和总结了有关研究设计、建模方法和结果的数据。大多数研究调查了在成人和儿童肾和肝移植中应用速释制剂后他克莫司的药代动力学。模型结构在很大程度上取决于研究采样策略，约50%的研究开发了使用谷浓度的一室模型和具有密集采样延迟吸收的两室模型。作为一个协变量，CYP3A5基因持续影响他克莫司清除量，并且需要调整剂量才能在患者中实现类似的药物暴露。许多协变量被确定为他克莫司药代动力学个体间变异的来源，这些研究的一致性有限，这可能是研究设计的结果。需要更多的分析来进一步评估这些协变量的潜在影响以及这些模型的临床应用，以指导他克莫司的剂量推荐。本文可能有助于指导未来人群药代动力学研究的设计，并为选择现有的最佳模型来个体化他克莫司治疗提供建议。
Tacrolimus, a calcineurin inhibitor, is a common immunosuppressant prescribed after organ transplantation and has notable inter- and intrapatient pharmacokinetic variability. The sources of variability have been investigated using population pharmacokinetic modeling over the last 2 decades. This article provides an updated synopsis on published nonlinear mixed-effects analyses developed for tacrolimus in transplant recipients. The objectives were to establish a detailed overview of the current data and to investigate covariate relationships determined by the models. Sixty-three published analyses were reviewed, and data regarding the study design, modeling approach, and resulting findings were extracted and summarized. Most of the studies investigated tacrolimus pharmacokinetics in adult and pediatric renal and liver transplants after administration of the immediate-release formulation. Model structures largely depended on the study sampling strategy, with ~50% of studies developing a 1-compartment model using trough concentrations and a 2-compartment model with delayed absorption from intensive sampling. The CYP3A5 genotype, as a covariate, consistently impacted tacrolimus clearance, and dosing adjustments were required to achieve similar drug exposure among patients. Numerous covariates were identified as sources of interindividual variability on tacrolimus pharmacokinetics with limited consistency across these studies, which may be the result of the study designs. Additional analyses are required to further evaluate the potential impact of these covariates and the clinical implementation of these models to guide tacrolimus dosing recommendations. This article may be useful for guiding the design of future population pharmacokinetic studies and provides recommendations for the selection of an existing optimal model to individualize tacrolimus therapy.
登录
查看更多内容
影响因子：
158.5
作者：
Ekberg, Henrik;Tedesco-Silva, Helio;Halloran, Philip F.
通讯作者：
Halloran, Philip F.
影响因子：
3.4
作者：
Antignac, Marie;Barrou, Benoit;Urien, Saik
通讯作者：
Urien, Saik
影响因子：
8.8
作者：
Bouamar, R.;Shuker, N.;van Gelder, T.
通讯作者：
van Gelder, T.
影响因子：
4.5
作者：
Benkali, Khaled;Rostaing, Lionel;Rousseau, Annick
通讯作者：
Rousseau, Annick
DOI：
10.1007/bf02353671
发表时间：
1996-06-01
期刊：
JOURNAL OF PHARMACOKINETICS AND BIOPHARMACEUTICS
影响因子：
--
作者：
Girard, P;Sheiner, LB;Blaschke, TF
通讯作者：
Blaschke, TF