Nonclinical juvenile toxicity testing

Evaluation of sitaxentan (Thelin®) toxicity in juvenile rats and regulatory interactions during the development of a European Medicines Agency pediatric investigation plan

“…The guidance text may have been intended to provide information on the age at which members of a species typically attain adulthood (defined as sexual maturity), thereby providing an age limit for treatment in a juvenile toxicity study, or may be interpreted as requiring that the treatment period in rats extend for 13 consecutive weeks. The interpretation of guidance used to support this study was that dosing should be timed to the developmental age of the animal corresponding with that of the pediatric population to be treated (Anderson et al, 2009;Beck et al, 2005). Using this interpretation, treatment would stop once sexual maturity was achieved.…”

Juvenile Animal Toxicity Studies: Regulatory Expectations, Decision Strategies and Role in Paediatric Drug Development

“…Alternatively, should they be viewed as general screening studies designed to evaluate all possible outcomes and to avoid missing any unique toxicity? In the first case, they serve as valuable adjunct studies to address specific concerns or fill a data gap whereas, in the second case, they rarely yield meaningful data for the assessment of paediatric safety (Baldrick, 2004;Brent, 2004;Beck et al, 2006;De Schaepdrijver et al, 2008. A scientific strategic approach, taking into account all clinical and nonclinical data and future development plans, is key.…”

“…As would be expected with a case-by-case approach, there are many permutations of the study specifics for these studies, for example, number of animals, end-points, dosing duration and recovery duration, and so on. For more information on these specific assessments, the reader is referred to other sources (De Schaepdrijver et al, 2009;Beck et al, 2006). Estimates are based on combined general developmental events occurring in both sexes, and represent only the overall schedule for CNS and reproductive development in these species.…”

Juvenile animal toxicity study designs to support pediatric drug development

“…This exposure period covers the postnatal period during which similar CNS and reproductive development occurs in rats and humans (Beck et al, 2006;Watson et al, 2006;Wood et al, 2003) from the youngest age for the intended pediatric population through adulthood. Behavioral testing occurs following the end of treatment as the objective of the study is to evaluate for potential long-term neurotoxicological consequences of exposure and not to identify potential pharmacologically-mediated effects.…”

“…PND 21 was selected for initiation of dosing since the liver in a PND-21 rat is similar in development to the liver in the youngest age of the pediatric population (Beck et al, 2006;Walthall et al, 2005). By dosing through PND 49, all relevant postnatal hepatic development occurring in the pediatric population will also occur in rats and the animals have initiated puberty allowing for evaluation of any potential effects on reproductive development (i.e., changes in the age at demonstration of balanopreputial separation and vaginal opening) (Beck et al, 2006;Beckman and Feuston, 2003;Marty et al, 2003;Walthall et al, 2005). Prior to terminal sacrifice, samples were collected for clinical pathology measurements.…”