a School of Pharmacy , University of Waterloo , Kitchener , Ontario , Canada.
Expert Opin Drug Metab Toxicol. 2018 Jun;14(6):585-599. doi: 10.1080/17425255.2018.1482278. Epub 2018 Jun 4.
Dose design for pediatric trials with monoclonal antibodies (mAbs) is often extrapolated from the adult dose according to weight, age, or body surface area. While these methods account for the size differences between adults and children, they do not account for the maturation of processes that may play a key role in the pharmacokinetics and/or pharmacodynamics of mAbs. With the same weight-based dose, infants and young children typically receive lower plasma exposures when compared to adults. Areas covered: The mechanistic features of mAb distribution, elimination, and absorption are explored in detail and literature-based hypotheses are generated to describe their age-dependence. This knowledge can be incorporated into a physiologically based pharmacokinetic (PBPK) modeling approach to pediatric dose determination. Expert opinion: As data from pediatric clinical trials become increasingly available, we have the opportunity to reflect on the physiologic drivers of pharmacokinetics, safety, and efficacy in children with mathematical models. A modeling approach that accounts for the age-related features of mAb disposition can be used to derive first-in-pediatric doses, design optimal sampling schemes for children in clinical trials and even explore new pharmacokinetic end-points as predictors of safety and efficacy in children.
儿科试验中使用单克隆抗体（mAbs）的剂量设计通常根据体重、年龄或体表面积从成人剂量推断而来。虽然这些方法考虑了成人和儿童之间的大小差异，但它们并未考虑到可能在 mAbs 的药代动力学和/或药效学中起关键作用的过程的成熟度。在相同基于体重的剂量下，与成人相比，婴儿和幼儿通常接受的血浆暴露量较低。涵盖的领域：详细探讨了 mAb 分布、消除和吸收的机制特征，并提出了基于文献的假设来描述其年龄依赖性。这些知识可以纳入基于生理学的药代动力学（PBPK）建模方法，以确定儿科剂量。专家意见：随着儿科临床试验数据的日益丰富，我们有机会通过数学模型来反思儿童药代动力学、安全性和疗效的生理驱动因素。一种能够解释 mAb 处置与年龄相关特征的建模方法可用于推导儿科首剂量，为临床试验中的儿童设计最佳采样方案，甚至探索新的药代动力学终点，作为儿童安全性和疗效的预测指标。
