title: Preclinical strategy to reduce clinical hepatotoxicity using in vitro bioactivation data for >200 compounds.
abstract: 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 <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of ≥100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding ≥200 pmol eq/mg protein tended to be hepatotoxic (∼ 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non-hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results.
authors.affiliation: Drug Metabolism and Pharmacokinetics, GlaxoSmithKline , Park Road, Ware, Hertfordshire SG12 0DP, United Kingdom. melanie.z.sakatis@gsk.com
authors.forename: Melanie Z
authors.initials: MZ
authors.lastname: Sakatis
authors.forename: Melinda J
authors.initials: MJ
authors.lastname: Reese
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Harrell
authors.forename: Maxine A
authors.initials: MA
authors.lastname: Taylor
authors.forename: Ian A
authors.initials: IA
authors.lastname: Baines
authors.forename: Liangfu
authors.initials: L
authors.lastname: Chen
authors.forename: Jackie C
authors.initials: JC
authors.lastname: Bloomer
authors.forename: Eric Y
authors.initials: EY
authors.lastname: Yang
authors.forename: Harma M
authors.initials: HM
authors.lastname: Ellens
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Ambroso
authors.forename: Cerys A
authors.initials: CA
authors.lastname: Lovatt
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Ayrton
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Clarke
mesh_terms: D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D003663:Decision Trees; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D064420:Drug-Related Side Effects and Adverse Reactions / Q000378:metabolism*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D004364:Pharmaceutical Preparations / Q000378:metabolism*; D011485:Protein Binding
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D004364:Pharmaceutical Preparations; D003577:Cytochrome P-450 Enzyme System; D005978:Glutathione