Physiologically Based Pharmacokinetic Modeling and Allometric Scaling in Pediatric Drug Development: Where Do We Draw the Line?
Physiologically Based Pharmacokinetic Modeling and Allometric Scaling in Pediatric Drug Development: Where Do We Draw the Line?
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DOI：
10.1002/jcph.1834
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发表时间：
2021-06-01
影响因子：
2.9
通讯作者：
Ke, Alice B.
中科院分区：
文献类型：
--
作者：
Johnson, Trevor N.;Ke, Alice B.
现在，美国和欧洲的立法都确立了为儿童开发药物的规定；新药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，许多发育过程不能通过简单的标量（如体重或体表面积）来反映，甚至基于简单异速缩放的预测剂量也可能导致某些年龄组的剂量明显过量。建模和仿真方法，包括基于生理学的建模，已经发展成为药物开发工具包的一部分，并越来越多地应用于儿科药物开发的各个方面。基于儿童生理的药代动力学（PBPK）模型解释了器官的发育和特定酶和转运体的个体发育，这些酶和转运体决定了与年龄相关的药代动力学特征。但是，什么时候应该使用这种方法，以及什么时候更简单的方法（如异速缩放）足以回答特定问题？本文旨在阐述异速缩放和PBPK在儿科药物开发中的应用，并结合案例探讨异速缩放和PBPK在儿科药物开发中的最佳应用。实际上，异速缩放作为人群药代动力学和PBPK方法的一部分，都是模型信息药物开发工具包的一部分，有助于药物发现和开发过程中的决策；为此目的，它们应被视为是互补的。
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.