Chapter 13. Non-Clinical Models for the Evaluation of Mechanisms of Toxicity

Advancing a new molecular entity into first-in-human clinical trials requires safety assessment in non-clinical animal models. This includes (but is not limited to) mammalian toxicology studies in two species, one rodent and one non-rodent, of at least equal duration to that intended for use in human trials. Historically, the species of choice for these studies have included the rat as the almost exclusive rodent species, and the beagle dog or cynomolgus monkey as the non-rodent species. However, other animal models are routinely used for a specific subset of regulated non-clinical safety studies, such as the rabbit and the mouse for reproductive toxicology and carcinogenicity studies, respectively. Still other animal models are widely used for mechanistic and/or regulatory pharmacotoxicology studies, including the ferret, pig, guinea pig, hamster, chinchilla, and zebrafish. Although these species are less frequently used in regulated studies to support regulatory submissions, they are often used as model systems to evaluate and understand pharmacology and toxicology in vivo. Understanding the mechanism of a dose-limiting toxicity can be critical to evaluating the potential risk to humans. The present chapter details some key parameters in selecting the most appropriate nonclinical animal models for regulatory and mechanistic toxicology assessment.