The application of discovery toxicology and pathology towards the design of safer pharmaceutical lead candidates

Toxicity is a leading cause of attrition at all stages of the drug development process. The majority of safety-related attrition occurs preclinically, suggesting that approaches to identify 'predictable' preclinical safety liabilities earlier in the drug development process could lead to the design and/or selection of better drug candidates that have increased probabilities of becoming marketed drugs. In this Review, we discuss how the early application of preclinical safety assessment - both new molecular technologies as well as more established approaches such as standard repeat- dose rodent toxicology studies - can identify predictable safety issues earlier in the testing paradigm. The earlier identification of dose-limiting toxicities will provide chemists and toxicologists the opportunity to characterize the dose-limiting toxicities, determine structure - toxicity relationships and minimize or circumvent adverse safety liabilities.