Department of Pharmacology and Toxicology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
Certara UK Limited, Sheffield, UK.
Pharmacol Ther. 2020 Jul;211:107541. doi: 10.1016/j.pharmthera.2020.107541. Epub 2020 Apr 1.
Developmental changes in children can affect the disposition and clinical effects of a drug, indicating that scaling an adult dose simply down per linear weight can potentially lead to overdosing, especially in very young children. Physiologically-based pharmacokinetic (PBPK) models are compartmental, mathematical models that can be used to predict plasma drug concentrations in pediatric populations and acquire insight into the influence of age-dependent physiological differences on drug disposition. Pediatric PBPK models have generated attention in the last decade, because physiological parameters for model building are increasingly available and regulatory guidelines demand pediatric studies during drug development. Due to efforts from academia, PBPK model developers, pharmaceutical companies and regulatory authorities, examples are now available where clinical studies in children have been replaced or informed by PBPK models. However, the number of pediatric PBPK models and their predictive performance still lags behind that of adult models. In this review we discuss the general pediatric PBPK model principles, indicate the challenges that can arise when developing models, and highlight new applications, to give an overview of the current status and future perspective of pediatric PBPK modeling.
儿童的发育变化会影响药物的处置和临床效果，这表明简单地按线性体重比例缩小成人剂量可能会导致药物过量，尤其是在非常年幼的儿童中。基于生理学的药代动力学（PBPK）模型是一种房室模型，可用于预测儿科人群中的血浆药物浓度，并深入了解年龄相关的生理差异对药物处置的影响。过去十年中，儿科 PBPK 模型引起了人们的关注，因为越来越多的模型构建生理参数可用，并且监管指南要求在药物开发期间进行儿科研究。由于学术界、PBPK 模型开发人员、制药公司和监管机构的努力，现在已经有一些例子可以用 PBPK 模型来替代或为儿童临床研究提供信息。然而，儿科 PBPK 模型的数量及其预测性能仍落后于成人模型。在这篇综述中，我们讨论了一般的儿科 PBPK 模型原则，指出了在模型开发过程中可能出现的挑战，并强调了新的应用，以概述儿科 PBPK 建模的现状和未来前景。
