Abstract
Efficacy studies in animal tumor models provide an early opportunity to collect preliminary information on toxicity. When screening and evaluating cytotoxic chemotherapeutic agents, efficacy studies usually include at least 1 dosage level that causes severe toxicity and death. Pathologic evaluation in early efficacy studies may reveal major target organs, dosage/schedule relationships, pharmacokinetic/toxicity relationships, effects of formulation and route of administration, maximum tolerated dose, cause of death, and reversibility of changes in normal tissues. Intraperitoneal formulations are frequently used to establish proof of concept for promising compounds (hits) from in vitro screens; however, these crude formulations may also induce intraperitoneal inflammation and confound the interpretation of both efficacy and toxicity. Efficacy studies conducted in the later stages of drug discovery may be used to refine the dose and schedule proposed for phase I clinical trials. Efficacy studies in animal tumor models provide useful toxicologic data for screening potential drug candidates, optimizing the therapeutic index, and designing both preclinical and clinical development programs.