title: Computational Models for Human and Animal Hepatotoxicity with a Global Application Scope.
abstract: Hepatic toxicity is a key concern for novel pharmaceutical drugs since it is difficult to anticipate in preclinical models, and it can originate from pharmacologically unrelated drug effects, such as pathway interference, metabolism, and drug accumulation. Because liver toxicity still ranks among the top reasons for drug attrition, the reliable prediction of adverse hepatic effects is a substantial challenge in drug discovery and development. To this end, more effort needs to be focused on the development of improved predictive in-vitro and in-silico approaches. Current computational models often lack applicability to novel pharmaceutical candidates, typically due to insufficient coverage of the chemical space of interest, which is either imposed by size or diversity of the training data. Hence, there is an urgent need for better computational models to allow for the identification of safe drug candidates and to support experimental design. In this context, a large data set comprising 3712 compounds with liver related toxicity findings in humans and animals was collected from various sources. The complex pathology was clustered into 21 preclinical and human hepatotoxicity endpoints, which were organized into three levels of detail. Support vector machine models were trained for each endpoint, using optimized descriptor sets from chemometrics software. The optimized global human hepatotoxicity model has high sensitivity (68%) and excellent specificity (95%) in an internal validation set of 221 compounds. Models for preclinical endpoints performed similarly. To allow for reliable prediction of "truly external" novel compounds, all predictions are tagged with confidence parameters. These parameters are derived from a statistical analysis of the predictive probability densities. The whole approach was validated for an external validation set of 269 proprietary compounds. The models are fully integrated into our early safety in-silico workflow.
authors.affiliation: R&D DSAR/Preclinical Safety FF, Sanofi-Aventis Deutschland GmbH , Industriepark Hoechst, Building H831, D-65926 Frankfurt am Main, Germany.
authors.forename: Denis
authors.initials: D
authors.lastname: Mulliner
authors.affiliation: R&D DSAR/Preclinical Safety FF, Sanofi-Aventis Deutschland GmbH , Industriepark Hoechst, Building H831, D-65926 Frankfurt am Main, Germany.
authors.forename: Friedemann
authors.initials: F
authors.lastname: Schmidt
authors.affiliation: R&D DSAR/Preclinical Safety FF, Sanofi-Aventis Deutschland GmbH , Industriepark Hoechst, Building H831, D-65926 Frankfurt am Main, Germany.
authors.forename: Manuela
authors.initials: M
authors.lastname: Stolte
authors.affiliation: R&D DSAR/Preclinical Safety FF, Sanofi-Aventis Deutschland GmbH , Industriepark Hoechst, Building H831, D-65926 Frankfurt am Main, Germany.
authors.forename: Hans-Peter
authors.initials: HP
authors.lastname: Spirkl
authors.affiliation: R&D DSAR/Preclinical Safety FF, Sanofi-Aventis Deutschland GmbH , Industriepark Hoechst, Building H831, D-65926 Frankfurt am Main, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Czich
authors.affiliation: R&D DSAR/Preclinical Safety FF, Sanofi-Aventis Deutschland GmbH , Industriepark Hoechst, Building H831, D-65926 Frankfurt am Main, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Amberg
mesh_terms: D000818:Animals; D019540:Area Under Curve; D003198:Computer Simulation; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008099:Liver / Q000187:drug effects*; D018675:Toxicity Tests