Mizuno Tomoyuki, Fukuda Tsuyoshi, Christians Uwe, Perentesis John P, Fouladi Maryam, Vinks Alexander A
Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Department of Pediatrics, College of Medicine, University of Cincinnati, Cincinnati, Ohio, USA.
Br J Clin Pharmacol. 2017 May;83(5):1097-1107. doi: 10.1111/bcp.13181. Epub 2016 Dec 20.
Temsirolimus is an inhibitor of the mammalian target of rapamycin (mTOR). Pharmacokinetic (PK) characterization of temsirolimus in children is limited and there is no paediatric temsirolimus population PK model available. The objective of this study was to simultaneously characterize the PK of temsirolimus and its metabolite sirolimus in paediatric patients with recurrent solid or central nervous system tumours and to develop a population PK model.
The PK data for temsirolimus and sirolimus were collected as a part of a Children's Oncology Group phase I clinical trial in paediatric patients with recurrent solid tumours. Serial blood concentrations obtained from 19 patients participating in the PK portion of the study were used for the analysis. Population PK analysis was performed by nonlinear mixed effect modelling using NONMEM.
A three-compartment model with zero-order infusion was found to best describe temsirolimus PK. Allometrically scaled body weight was included in the model to account for body size differences. Temsirolimus dose was identified as a significant covariate on clearance. A sirolimus metabolite formation model was developed and integrated with the temsirolimus model. A two-compartment structure model adequately described the sirolimus data.
This study is the first to describe a population PK model of temsirolimus combined with sirolimus formation and disposition in paediatric patients. The developed model will facilitate PK model-based dose individualization of temsirolimus and the design of future clinical studies in children.
替西罗莫司是一种雷帕霉素哺乳动物靶点（mTOR）抑制剂。替西罗莫司在儿童中的药代动力学（PK）特征有限，且尚无儿科替西罗莫司群体PK模型。本研究的目的是同时描述替西罗莫司及其代谢产物西罗莫司在患有复发性实体瘤或中枢神经系统肿瘤的儿科患者中的PK，并建立一个群体PK模型。
作为儿童肿瘤学组针对患有复发性实体瘤的儿科患者进行的I期临床试验的一部分，收集了替西罗莫司和西罗莫司的PK数据。从参与该研究PK部分的19名患者获得的系列血药浓度用于分析。使用NONMEM通过非线性混合效应建模进行群体PK分析。
发现具有零级输注的三室模型最能描述替西罗莫司的PK。模型中纳入了根据体表面积校正的体重以考虑体型差异。替西罗莫司剂量被确定为清除率的一个显著协变量。建立了西罗莫司代谢产物形成模型并与替西罗莫司模型整合。一个二室结构模型充分描述了西罗莫司的数据。
本研究首次描述了替西罗莫司与西罗莫司形成及处置相结合的儿科患者群体PK模型。所建立的模型将有助于基于PK模型的替西罗莫司剂量个体化以及未来儿童临床研究的设计。
