title: The application of discovery toxicology and pathology towards the design of safer pharmaceutical lead candidates.
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.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Lexicon Pharmaceuticals Inc., 8800 Technology Forest Place, The Woodlands, Texas 77381, USA. jkramer@lexpharma.com
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Kramer
authors.forename: John E
authors.initials: JE
authors.lastname: Sagartz
authors.forename: Dale L
authors.initials: DL
authors.lastname: Morris
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008954:Models, Biological; D010597:Pharmacogenetics / Q000379:methods; D013678:Technology, Pharmaceutical / Q000379:methods*; D018675:Toxicity Tests