Preclinical Strategy to Reduce Clinical Hepatotoxicity Using in Vitro Bioactivation Data for >200 Compounds

• Published in: Chemical research in toxicology 2012-10, Vol.25 (10), p.2067-2082
• Main Authors: Sakatis, Melanie Z, Reese, Melinda J, Harrell, Andrew W, Taylor, Maxine A, Baines, Ian A, Chen, Liangfu, Bloomer, Jackie C, Yang, Eric Y, Ellens, Harma M, Ambroso, Jeffrey L, Lovatt, Cerys A, Ayrton, Andrew D, Clarke, Stephen E
• Format: Article
• Language: English
• Subjects: Chemical and Drug Induced Liver Injury - metabolism; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System - metabolism; Decision Trees; Drug Evaluation, Preclinical - methods; Drug-Related Side Effects and Adverse Reactions - metabolism; Glutathione - metabolism; Humans; Liver - drug effects; Liver - metabolism; Pharmaceutical Preparations - metabolism; Protein Binding
• ISSN: 0893-228X; 1520-5010
• DOI: 10.1021/tx300075j

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of