INSERM UMR 1248, Université de Limoges, FHU support, Limoges Cédex, 87025, France.
Federal Agency for Medicines and Health Products, Brussels, Belgium.
Br J Clin Pharmacol. 2019 Dec;85(12):2793-2823. doi: 10.1111/bcp.14110. Epub 2019 Dec 17.
The objective of this study is to develop a generic model for tacrolimus pharmacokinetics modelling using a meta-analysis approach, that could serve as a first step towards a prediction tool to inform pharmacokinetics-based optimal dosing of tacrolimus in different populations and indications.
A systematic literature review was performed and a meta-model developed with NONMEM software using a top-down approach. Historical (previously published) data were used for model development and qualification. In-house individual rich and sparse tacrolimus blood concentration profiles from adult and paediatric kidney, liver, lung and heart transplant patients were used for model validation. Model validation was based on successful numerical convergence, adequate precision in parameter estimation, acceptable goodness of fit with respect to measured blood concentrations with no indication of bias, and acceptable performance of visual predictive checks. External validation was performed by fitting the model to independent data from 3 external cohorts and remaining previously published studies.
A total of 76 models were found relevant for meta-model building from the literature and the related parameters recorded. The meta-model developed using patient level data was structurally a 2-compartment model with first-order absorption, absorption lag time and first-time varying elimination. Population values for clearance, intercompartmental clearance, central and peripheral volume were 22.5 L/h, 24.2 L/h, 246.2 L and 109.9 L, respectively. The absorption first-order rate and the lag time were fixed to 3.37/h and 0.33 hours, respectively. Transplanted organ and time after transplantation were found to influence drug apparent clearance whereas body weight influenced both the apparent volume of distribution and the apparent clearance. The model displayed good results as regards the internal and external validation.
A meta-model was successfully developed for tacrolimus in solid organ transplantation that can be used as a basis for the prediction of concentrations in different groups of patients, and eventually for effective dose individualization in different subgroups of the population.
本研究旨在通过荟萃分析方法建立一个通用的他克莫司药代动力学模型，为不同人群和适应证的基于药代动力学的他克莫司最佳给药剂量预测工具奠定基础。
采用自上而下的方法，通过 NONMEM 软件进行系统文献回顾和荟萃模型开发。历史（已发表）数据用于模型开发和验证。使用来自成人和儿科肾、肝、肺和心脏移植患者的个体化丰富和稀疏他克莫司血药浓度数据进行模型验证。模型验证基于数值收敛成功、参数估计具有足够的精度、与实测血药浓度拟合良好且无偏差、以及视觉预测检查的性能良好。通过将模型拟合到 3 个外部队列和其余先前发表的研究的独立数据进行外部验证。
从文献和相关参数记录中总共找到了 76 个与荟萃模型构建相关的模型。使用患者水平数据开发的荟萃模型在结构上是一个 2 室模型，具有一级吸收、吸收滞后时间和首次时变消除。清除率、隔室清除率、中央和外周体积的群体值分别为 22.5 L/h、24.2 L/h、246.2 L 和 109.9 L。吸收一级速率和滞后时间分别固定为 3.37/h 和 0.33 小时。发现移植器官和移植后时间影响药物表观清除率，而体重影响表观分布体积和表观清除率。该模型在内部和外部验证方面表现良好。
成功建立了用于实体器官移植的他克莫司荟萃模型，可用于预测不同患者群体的浓度，并最终实现人群不同亚组的有效剂量个体化。
