An assessment of a toxicological incident in a drug development program and its implications

In an exceptionally thorough program of preclinical toxicity testing in laboratory animals of the anti-allergy drug FPL 52757 (6,8-diethyl-5-hydroxy-4-oxo-4H-1-benzopyran-2-carboxylic acid), no significant hepatotoxic potential was detected. Despite this evidence of safety in a wide range of laboratory animals, the drug produced mild reversible hepatotoxicity in some patients in some clinical trials. Extensive toxicity and investigational studies are described, and the importance of the correct choice of species for toxicology evaluations based on sound pharmacokinetic principles is highlighted. This paper reviews this incident and the lessons to be learned from it in light of current regulatory requirements.