Use of Data from Transgenic Animals in Safety Pharmacology

Safety pharmacology addresses the adverse functional (i.e., pharmacodynamic) responses to drugs. Detecting and assessing functional responses involves measuring biochemical, physiological, and behavioral changes, using both in vitro and in vivo techniques. Safety pharmacology focuses on five organ systems, namely, the cardiovascular system, nervous system, respiratory system, gastrointestinal system, and renal system. Applications of genetically modified animals in safety pharmacology currently lag behind other areas within drug discovery, including toxicology. Part of the reason for this is the reduction in quality of physiological and behavioral data obtained from the (transgenic) mouse compared to the rat, which is the rodent species of choice in safety pharmacology. Whereas many safety pharmacologists routinely incorporate published data on knockout mice into on-target and off-target risk assessment, the use of transgenic animals in mechanistic studies is only done on a very ad hoc basis. This chapter explores some potential applications of transgenic animals (or published phenotyping of transgenic knockout animals) in safety pharmacology, including on-target and off-target risk assessment, pharmacodynamic and pharmacokinetic mechanistic studies, use of “humanized” transgenic animals, and altering the physiological baseline and reporter genes.