Use of In Vivo Animal Models to Assess Drug-Drug Interactions

In this chapter, theoretical basis and specific examples are presented to illustrate the utility of the animal models in assessing and understanding the underlying mechanisms of DDIs. In vivo assessments in an appropriate animal model are considered key to help verify in vivo relevance of in vitro studies and substantiate a basis for extrapolating in vitro human data to clinical outcomes. From a pharmacokinetic standpoint, an important consideration for successful selection of the animal model is based on broad similarities to humans in key physiological and biochemical parameters governing drug absorption, distribution, metabolism, or excretion (ADME) process of interest for both the interacted and the interacting drugs. Also equally important are specific in vitro and/or in vivo experiments demonstrating animal human similarities, usually both qualitative and quantitative, in the ADME property/process under investigation. Additional insights can also be gained with the use of knockout animals lacking specific drug transporters or drug-metabolizing enzymes and/or transgenic animal models with humanized mouse lines expressing specific drug transporters and/or metabolizing enzymes of interest.