Species Selection for Pharmaceutical Toxicity Studies

Abstract

Selecting the most appropriate animal species for toxicity testing increases the likelihood of detecting potential effects in humans. Regulatory guidelines provide a framework for the development of appropriate and meaningful nonclinical programs for both chemically synthesized pharmaceuticals and biotherapeutic products. In the case of small molecules, a key factor in species selection is determining the metabolic profiles (similarities and differences) between candidate species and human. For biotherapeutics, species selection is based on pharmacological relevance (expressed target receptor or epitope and appropriate functional engagement) that evokes a similar pharmacological response as that expected in humans. The rat is the predominant rodent species of choice based on size and extensive historical database. The rationale for selecting the appropriate nonrodent species among commonly used toxicology species including dog, minipig, rabbit, and nonhuman primate (NHP) is more challenging and should be a science-based and data driven decision to meet regulatory expectations and not a default to a preferred species. In particular, the use of the NHP should be scientifically and ethically justified in terms of benefits and pharmacological relevance, as well as consideration to the 3R principles. This chapter aims to provide an introduction to the selection of relevant animal species for toxicology studies for small molecules and biotherapeutics. A firm understanding of the regulatory requirements for pharmaceuticals for human use will ensure that the most sensitive and regulatory-compliant animal species are utilized to maximize the chances of gaining regulatory approval for clinical testing or market authorization in the shortest time frame.