Certara UK Limited, Sheffield, UK.
Certara USA, Inc., Princeton, New Jersey, USA.
J Clin Pharmacol. 2021 Jun;61 Suppl 1:S83-S93. doi: 10.1002/jcph.1834.
Developing medicines for children is now established in legislation in both the United States and Europe; new drugs require pediatric study or investigation plans as part of their development. Particularly in early age groups, many developmental processes are not reflected by simple scalars such as body weight or body surface area, and even projecting doses based on simple allometric scaling can lead to significant overdoses in certain age groups. Modeling and simulation methodology, including physiologically based modeling, has evolved as part of the drug development toolkit and is being increasingly applied to various aspects of pediatric drug development. Pediatric physiologically based pharmacokinetic (PBPK) models account for the development of organs and the ontogeny of specific enzymes and transporters that determine the age-related pharmacokinetic profiles. However, when should this approach be used, and when will simpler methods such as allometric scaling suffice in answering specific problems? The aim of this review article is to illustrate the application of allometric scaling and PBPK in pediatric drug development and explore the optimal application of the latter approach with reference to case examples. In reality, allometric scaling included as part of population pharmacokinetic and PBPK approaches are all part of a model-informed drug development toolkit helping with decision making during the process of drug discovery and development; to that end, they should be viewed as complementary.
为儿童开发药物现在已经在美国和欧洲的立法中得到确立；新药物需要儿科研究或调查计划作为其开发的一部分。特别是在早期年龄组中，许多发育过程不能通过体重或体表面积等简单标度来反映，即使基于简单的比例缩放来预测剂量，也会导致某些年龄组出现明显的过量。建模和模拟方法学，包括基于生理学的建模，已经作为药物开发工具包的一部分发展起来，并越来越多地应用于儿科药物开发的各个方面。儿科生理药代动力学（PBPK）模型考虑了器官的发育和特定酶和转运体的个体发生，这些决定了与年龄相关的药代动力学特征。然而，何时应该使用这种方法，何时简单的比例缩放方法就足以回答特定问题？本文的目的是举例说明比例缩放和 PBPK 在儿科药物开发中的应用，并探讨后者方法的最佳应用。实际上，作为群体药代动力学和 PBPK 方法一部分的比例缩放，都是模型指导药物开发工具包的一部分，有助于在药物发现和开发过程中进行决策；为此，它们应被视为互补的。
