title: Minimizing DILI risk in drug discovery - A screening tool for drug candidates.
abstract: Drug-induced liver injury (DILI) is a leading cause of acute hepatic failure and a major reason for market withdrawal of drugs. Idiosyncratic DILI is multifactorial, with unclear dose-dependency and poor predictability since the underlying patient-related susceptibilities are not sufficiently understood. Because of these limitations, a pharmaceutical research option would be to reduce the compound-related risk factors in the drug-discovery process. Here we describe the development and validation of a methodology for the assessment of DILI risk of drug candidates. As a training set, 81 marketed or withdrawn compounds with differing DILI rates - according to the FDA categorization - were tested in a combination of assays covering different mechanisms and endpoints contributing to human DILI. These include the generation of reactive metabolites (CYP3A4 time-dependent inhibition and glutathione adduct formation), inhibition of the human bile salt export pump (BSEP), mitochondrial toxicity and cytotoxicity (fibroblasts and human hepatocytes). Different approaches for dose- and exposure-based calibrations were assessed and the same parameters applied to a test set of 39 different compounds. We achieved a similar performance to the training set with an overall accuracy of 79% correctly predicted, a sensitivity of 76% and a specificity of 82%. This test system may be applied in a prospective manner to reduce the risk of idiosyncratic DILI of drug candidates.
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: simone.schadt@roche.com.
authors.forename: S
authors.initials: S
authors.lastname: Schadt
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: silke.simon@roche.com.
authors.forename: S
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authors.lastname: Simon
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: stefan.kustermann@roche.com.
authors.forename: S
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authors.lastname: Kustermann
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: franziska.boess@roche.com.
authors.forename: F
authors.initials: F
authors.lastname: Boess
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: claudia.mcginnis@roche.com.
authors.forename: C
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authors.lastname: McGinnis
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: andreas.brink@roche.com.
authors.forename: A
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authors.lastname: Brink
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: rebecca.lieven@roche.com.
authors.forename: R
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authors.lastname: Lieven
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: stephen.fowler@roche.com.
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authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: kuresh.youdim@roche.com.
authors.forename: K
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authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: mohammed.ullah@roche.com.
authors.forename: M
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authors.lastname: Ullah
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: michaela.marschmann@roche.com.
authors.forename: M
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authors.lastname: Marschmann
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: christine.zihlmann@roche.com.
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authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: yves_martin.siegrist@roche.com.
authors.forename: Y M
authors.initials: YM
authors.lastname: Siegrist
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: anne-christine.cascais@roche.com.
authors.forename: A C
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authors.lastname: Cascais
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: elisa.di_lenarda@roche.com.
authors.forename: E
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authors.lastname: Di Lenarda
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: evelyne.durr@roche.com.
authors.forename: E
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authors.lastname: Durr
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: nathalie.schaub@roche.com.
authors.forename: N
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authors.lastname: Schaub
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland.
authors.forename: X
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authors.lastname: Ang
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: volkmar.starke@roche.com.
authors.forename: V
authors.initials: V
authors.lastname: Starke
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: thomas.singer@roche.com.
authors.forename: T
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authors.lastname: Singer
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: ruben.alvarez_sanchez@roche.com.
authors.forename: R
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authors.lastname: Alvarez-Sanchez
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: adrian_b.roth@roche.com.
authors.forename: A B
authors.initials: AB
authors.lastname: Roth
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: franz.schuler@roche.com.
authors.forename: F
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authors.lastname: Schuler
authors.affiliation: Pharmaceutical Sciences, Roche Pharma Research and Early Development, Roche Innovation Center Basel, F. Hoffmann-La Roche Ltd., Grenzacher Str. 124, 4070 Basel, Switzerland. Electronic address: christoph.funk@roche.com.
authors.forename: C
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authors.lastname: Funk
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000037:antagonists & inhibitors; D000818:Animals; D002138:Calibration; D056486:Chemical and Drug Induced Liver Injury; D055808:Drug Discovery; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D005978:Glutathione / Q000378:metabolism; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells
chemical_list: C093491:ABCB11 protein, human; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; D005978:Glutathione
keywords: BSEP inhibition; Cytotoxicity; DILI assessment; Hepatotoxicity; Liver injury; Mitochondrial toxicity; Reactive metabolites