Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH 4070 Basel, Switzerland.
Roche Pharmaceutical Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacherstrasse 124, CH 4070 Basel, Switzerland.
Reprod Toxicol. 2022 Sep;112:77-87. doi: 10.1016/j.reprotox.2022.06.010. Epub 2022 Jun 27.
This review focuses on preweaning ontogenic and developmental processes that can influence the selection of the appropriate age at which to start dosing rodent pups in juvenile animal studies (JAS). The ICH S11 guideline on 'Nonclinical Safety Testing in Support of Development of Paediatric Medicines' highlights the need to adapt the age from which animals are dosed according to the stage of development in the target organs/tissues of concern in the youngest pediatric patients. Rodents (rat or mouse) are the most common species for JAS. Despite previous practices, based on comparative ontogeny, it is rarely necessary to dose rodents younger than one week of age since postnatal day (PND)7 is appropriate to address concern for the vast majority of organs. In exceptional cases, earlier dosing (e.g., PND4) can be appropriate to address specific concern in preterm neonates and when a tissue of concern has a particularly early developmental trajectory in the rodent compared to humans. The comparative development of the CNS is particularly complex. While exposure of rodents from PND10 covers most CNS development stages relevant to human neonates, a later dosing start (yet, not later than PND14) can sometimes be appropriate to reflect specific aspects (e.g., transformation of GABAergic transmission). An extended study design including subsets of several ages can be helpful to address multiple concerns within a preweaning JAS. Such design can allow for individual assessment of each concern, whilst minimizing (potentially irrelevant) signals from tissues exposed at a developmental stage that do not match the human situation.
这篇综述重点介绍了新生动物期和发育期的发育过程，这些过程可能会影响选择开始对幼年动物研究（JAS）中的幼鼠进行剂量给药的适当年龄。ICH S11 指南“儿科药物非临床安全性测试”强调了根据目标器官/组织中最年幼儿科患者的发育阶段来调整开始给药的年龄的必要性。啮齿动物（大鼠或小鼠）是 JAS 中最常用的物种。尽管有先前的做法，但基于比较发育，很少有必要对小于一周龄的啮齿动物进行给药，因为 PND7 适合解决绝大多数器官的担忧。在特殊情况下，更早的给药（例如 PND4）可能适合解决早产儿的特定担忧，以及当关注的组织在啮齿动物中的发育轨迹比人类更早时。中枢神经系统的比较发育特别复杂。虽然从 PND10 开始对啮齿动物进行暴露可以涵盖与人类新生儿相关的大多数 CNS 发育阶段，但有时可以适当开始较晚的给药（但不迟于 PND14），以反映特定方面（例如 GABA 能传递的转化）。一个包括几个年龄段的子集的扩展研究设计可以有助于解决 JAS 前的多个问题。这种设计可以允许对每个问题进行单独评估，同时最小化（可能不相关）来自与人类情况不匹配的发育阶段暴露的组织的信号。
