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  • Perspective
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Managing the challenge of drug-induced liver injury: a roadmap for the development and deployment of preclinical predictive models

Nature Reviews Drug Discovery volume 19, pages 131–148 (2020)Cite this article

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Abstract

Drug-induced liver injury (DILI) is a patient-specific, temporal, multifactorial pathophysiological process that cannot yet be recapitulated in a single in vitro model. Current preclinical testing regimes for the detection of human DILI thus remain inadequate. A systematic and concerted research effort is required to address the deficiencies in current models and to present a defined approach towards the development of new or adapted model systems for DILI prediction. This Perspective defines the current status of available models and the mechanistic understanding of DILI, and proposes our vision of a roadmap for the development of predictive preclinical models of human DILI.

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Fig. 1: Various chemical insults can lead to diverse clinical manifestations of DILI.
Fig. 2: Roadmap for the development of ‘fit-for-purpose’ predictive models of human DILI.
Fig. 3: Hepatocyte couplet illustrating the basolateral and canalicular location of transport proteins.
Fig. 4: Role of the adaptive immune system in DILI.

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Acknowledgements

This work was supported by the European Community (Contract MIP-DILI-115336) under the Innovative Medicines Initiative Joint Undertaking, a contribution from the European Union's Seventh Framework Programme (FP7/20072013) and European Federation of Pharmaceutical Industries and Associations (EFPIA) companies (http://www.imi.europa.eu/) and by the German Ministry of Education and Research (BMBF) within ‘Multi-Scale Modeling of Drug-Induced Liver Injury’ (MS_DILI, 031L0074A). The authors would like to thank K. Clayson for her excellent administrative role in the preparation and coordination of this article.

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Authors and Affiliations

  1. Biopharmacy, Institute de Recherches Internationales Servier, Suresnes, France

    Richard J. Weaver

  2. Global Preclinical Safety, Abbvie, North Chicago, IL, USA

    Eric A. Blomme & Michael J. Liguori

  3. Department of Molecular and Clinical Pharmacology, MRC Centre for Drug Safety Science, University of Liverpool, Liverpool, UK

    Amy E. Chadwick, Ian M. Copple, Christopher E. Goldring, Dean J. Naisbitt & B. Kevin Park

  4. Development Science, UCB BioPharma SPRL, Braine-l’Alleud, Belgium

    Helga H. J. Gerets

  5. INSERM, INRA, Institut NUMECAN (Nutrition Metabolisms and Cancer), UMR_S 1241, University Rennes, Rennes, France

    Andre Guillouzo

  6. Chemical and Preclinical Safety, Merck Healthcare KGaA, Darmstadt, Germany

    Philip G. Hewitt

  7. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden

    Magnus Ingelman-Sundberg

  8. Drug ADME Research, H. Lundbeck A/S, Valby, Denmark

    Klaus Gjervig Jensen

  9. In Vitro Biology, Orion Pharma, Espoo, Finland

    Satu Juhila

  10. Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany

    Ursula Klingmüller

  11. Investigative Toxicology, Preclinical Safety, Sanofi R&D, Paris, France

    Gilles Labbe

  12. Non-Clinical Safety, GlaxoSmithKline, Ware, UK

    Cerys A. Lovatt

  13. Clinical Pharmacology and Safety Sciences, Biopharmaceuticals Science Unit, AstraZeneca, Cambridge, UK

    Paul Morgan & Dominic P. Williams

  14. Immunotoxicology, Faculty of Veterinary Medicines, Institute for Risk Assessment Sciences, Utrecht University, Utrecht, Netherlands

    Raymond H. H. Pieters

  15. Drug Metabolism and Pharmacokinetics, Janssen Research and Development, Beerse, Belgium

    Jan Snoeys

  16. Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, Netherlands

    Bob van de Water

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  1. Richard J. Weaver
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Correspondence to Richard J. Weaver or B. Kevin Park.

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Competing interests

E.A.B. and M.J.L are employees of Abbvie. H.H.J.G. is an employee of UCB BioPharma SPRL. P.G.H. is an employee of Merck KGaA. K.G.J. is an employee of H Lundbeck. S.J. is an employee of Orion Pharma. G.L. is an employee of Sanofi. C.A.L. is an employee of GlaxoSmithKline. P.M. is an employee of AstraZeneca. J.S. is an employee of Janssen Research and Development.

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Weaver, R.J., Blomme, E.A., Chadwick, A.E. et al. Managing the challenge of drug-induced liver injury: a roadmap for the development and deployment of preclinical predictive models. Nat Rev Drug Discov 19, 131–148 (2020). https://doi.org/10.1038/s41573-019-0048-x

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