Zhao W, Elie V, Roussey G, Brochard K, Niaudet P, Leroy V, Loirat C, Cochat P, Cloarec S, André J L, Garaix F, Bensman A, Fakhoury M, Jacqz-Aigrain E
Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, Paris, France.
Clin Pharmacol Ther. 2009 Dec;86(6):609-18. doi: 10.1038/clpt.2009.210. Epub 2009 Oct 28.
The aim of this study was to develop a population pharmacokinetic model of tacrolimus in pediatric kidney transplant patients, identify factors that explain variability, and determine dosage regimens. Pharmacokinetic samples were collected from 50 de novo pediatric kidney transplant patients (age 2-18 years) who were on tacrolimus treatment. Population pharmacokinetic analysis of tacrolimus was performed using NONMEM, and the impact of variables (demographic and clinical factors, and CYP3A4-A5, ABCB1, and ABCC2 polymorphisms) was tested. The pharmacokinetic data were described by a two-compartment model that incorporated first-order absorption and lag time. The apparent oral clearance (CL/F) was significantly related to body weight (allometric scaling); in addition, it was higher in patients with low hematocrit levels and lower in patients with CYP3A5*3/*3. The population pharmacokinetic-pharmacogenetic model developed in de novo pediatric kidney transplant patients demonstrated that, in children, tacrolimus dosage should be based on weight, hematocrit levels, and CYP3A5 polymorphism. Individualization of therapy will enable the optimization of tacrolimus exposure, with resultant beneficial effects on kidney function in the initial post-transplantation period.
本研究的目的是建立小儿肾移植患者他克莫司的群体药代动力学模型，识别解释变异性的因素，并确定给药方案。从50例接受他克莫司治疗的初治小儿肾移植患者（年龄2至18岁）中收集药代动力学样本。使用NONMEM对他克莫司进行群体药代动力学分析，并测试变量（人口统计学和临床因素，以及CYP3A4 - A5、ABCB1和ABCC2基因多态性）的影响。药代动力学数据用包含一级吸收和滞后时间的二室模型描述。表观口服清除率（CL/F）与体重显著相关（异速生长标度）；此外，血细胞比容水平低的患者其值较高，而携带CYP3A5*3/*3的患者其值较低。在初治小儿肾移植患者中建立的群体药代动力学 - 药物遗传学模型表明，在儿童中，他克莫司剂量应基于体重、血细胞比容水平和CYP3A5基因多态性。个体化治疗将能够优化他克莫司的暴露量，从而在移植后的初始阶段对肾功能产生有益影响。
