Abstract

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.

Author affiliations

1. Department of Drug Metabolism and Pharmacokinetics, Lexicon Pharmaceuticals Inc., 8800 Technology Forest Place, The Woodlands, Texas 77381, USA.
2. Seventh Wave Laboratories, Suite 209, 743 Spirit 40 Park Drive, Chesterfield, Missouri 63005, USA.
3. Drug Safety Research and Development, Pfizer Inc., 700 Chesterfield Parkway West T1A, Chesterfield, Missouri 63017, USA.

Correspondence to: Jeffrey A. Kramer¹ Email: jkramer@lexpharma.com