title: Evidence-based selection of training compounds for use in the mechanism-based integrated prediction of drug-induced liver injury in man.
abstract: The current test systems employed by pharmaceutical industry are poorly predictive for drug-induced liver injury (DILI). The 'MIP-DILI' project addresses this situation by the development of innovative preclinical test systems which are both mechanism-based and of physiological, pharmacological and pathological relevance to DILI in humans. An iterative, tiered approach with respect to test compounds, test systems, bioanalysis and systems analysis is adopted to evaluate existing models and develop new models that can provide validated test systems with respect to the prediction of specific forms of DILI and further elucidation of mechanisms. An essential component of this effort is the choice of compound training set that will be used to inform refinement and/or development of new model systems that allow prediction based on knowledge of mechanisms, in a tiered fashion. In this review, we focus on the selection of MIP-DILI training compounds for mechanism-based evaluation of non-clinical prediction of DILI. The selected compounds address both hepatocellular and cholestatic DILI patterns in man, covering a broad range of pharmacologies and chemistries, and taking into account available data on potential DILI mechanisms (e.g. mitochondrial injury, reactive metabolites, biliary transport inhibition, and immune responses). Known mechanisms by which these compounds are believed to cause liver injury have been described, where many if not all drugs in this review appear to exhibit multiple toxicological mechanisms. Thus, the training compounds selection offered a valuable tool to profile DILI mechanisms and to interrogate existing and novel in vitro systems for the prediction of human DILI.
authors.affiliation: AIMMS Section of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, VU University Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands.
authors.forename: Sanja
authors.initials: S
authors.lastname: Dragovic
authors.affiliation: AIMMS Section of Molecular Toxicology, Department of Chemistry and Pharmaceutical Sciences, VU University Amsterdam, De Boelelaan 1108, 1081 HZ, Amsterdam, The Netherlands. n.p.e.vermeulen@vu.nl.
authors.forename: Nico P E
authors.identifier: http://orcid.org/0000-0003-4194-6401
authors.initials: NP
authors.lastname: Vermeulen
authors.affiliation: UCB BioPharma SPRL, Non-Clinical Development, Chemin du Foriest, 1420, Braine-l'Alleud, Belgium.
authors.forename: Helga H
authors.initials: HH
authors.lastname: Gerets
authors.affiliation: Early Non-Clinical Safety, Merck KGaA, Frankfurter Str. 250, 64293, Darmstadt, Germany.
authors.forename: Philip G
authors.initials: PG
authors.lastname: Hewitt
authors.affiliation: Department of Physiology and Pharmacology, Section of Pharmacogenetics, Karolinska Institutet, 171 77, Stockholm, Sweden.
authors.forename: Magnus
authors.initials: M
authors.lastname: Ingelman-Sundberg
authors.affiliation: MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, University of Liverpool, Sherrington Building, Ashton Street, Liverpool, L69 3GE, UK.
authors.forename: B Kevin
authors.initials: BK
authors.lastname: Park
authors.affiliation: Orion Pharma, R&D In Vitro Biology, Orionintie 1A, P.O. Box 65, 02101, Espoo, Finland.
authors.forename: Satu
authors.initials: S
authors.lastname: Juhila
authors.affiliation: Pharmacokinetics, Dynamics and Metabolism, Janssen R&D, Turnhoutseweg 30, 2340, Beerse, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Snoeys
authors.affiliation: Institut de Recherches Internationales Servier (I.R.I.S.), 50, rue Carnot, 92284, Suresnes Cedex, France.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Weaver
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects; D000818:Animals; D001185:Artificial Intelligence; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D019295:Computational Biology / Q000379:methods*; D015507:Drugs, Investigational / Q000009:adverse effects* / Q000737:chemistry / Q000145:classification / Q000494:pharmacology; D019317:Evidence-Based Medicine; D005103:Expert Systems; D065669:Hepatobiliary Elimination / Q000187:drug effects; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D008247:Lysosomes / Q000187:drug effects / Q000378:metabolism; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism; D008954:Models, Biological; D015394:Molecular Structure; D018384:Oxidative Stress / Q000187:drug effects; D012720:Severity of Illness Index
chemical_list: D015507:Drugs, Investigational
keywords: DILI mechanisms; Drug-induced liver injury (DILI); Evidence-based selection; MIP-DILI; Set of training compounds