Considerations for and against dosing rodent pups before 7 days of age in juvenile toxicology studies.

ABSTRACT

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.