Safety pharmacology screening: Practical problems in drug development

Undesired pharmacologic activities of novel drugs or biologics may limit development of a therapeutic prior to the characterization of any toxicologic effects. In rodent species, general pharmacology assays have traditionally been used to screen new agents for pharmacologic effects on the central and peripheral nervous systems, the autonomic nervous system and smooth muscles, the respiratory and cardiovascular systems, the digestive system, and the physiologic mechanisms of water and electrolyte balance. In large animal species, such as dogs and nonhuman primates, smaller numbers of animals per study limit their we for screening assays, but these species may play an important role in. more detailed mechanistic studies. For drugs and biologics that must be tested in. nonhuman primates because of species-specific action of the test agent, functional pharmacologic data are often collected during acute or subacute toxicity studies. This requires careful experimental design to minimize any impact pharmacologic effects or instrumentation may have on the assessment of toxicity. In addition, with many new therapies targeted at immunologic diseases, the pharmacologic effect of therapeutics on the immune system presents new challenges for pharmacologic profiling. The application of pharmacology assays by organ system in both rodent and large animal species are discussed, as well as practical issues in assessing pharmacology endpoints in the context of toxicity studies.