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

• Published in: Nature reviews. Drug discovery Vol. 19; no. 2; pp. 131 - 148
• Main Authors: Weaver, Richard J., Blomme, Eric A., Chadwick, Amy E., Copple, Ian M., Gerets, Helga H. J., Goldring, Christopher E., Guillouzo, Andre, Hewitt, Philip G., Ingelman-Sundberg, Magnus, Jensen, Klaus Gjervig, Juhila, Satu, Klingmüller, Ursula, Labbe, Gilles, Liguori, Michael J., Lovatt, Cerys A., Morgan, Paul, Naisbitt, Dean J., Pieters, Raymond H. H., Snoeys, Jan, van de Water, Bob, Williams, Dominic P., Park, B. Kevin
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-02-2020; Nature Publishing Group
• Subjects: 631/154; 692/308/2778; 692/700/565/2194; Animals; Biomedical and Life Sciences; Biomedicine; Biotechnology; Cancer Research; Chemical and Drug Induced Liver Injury - diagnosis; Chemical and Drug Induced Liver Injury - etiology; Disease Models, Animal; Drug-Related Side Effects and Adverse Reactions - prevention & control; Drugs; Human health and pathology; Humans; Hépatology and Gastroenterology; Life Sciences; Liver; Medicin och hälsovetenskap; Medicinal Chemistry; Molecular Medicine; Mortality; Perspective; Pharmaceutical industry; Pharmacology/Toxicology; Physiology; Predictive Value of Tests; Test systems; Adverse effects; Drug discovery; Preclinical research
• ISSN: 1474-1776; 1474-1784; 1474-1784
• DOI: 10.1038/s41573-019-0048-x

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.
Current preclinical models poorly predict the potential of a new drug candidate to cause drug-induced liver injury (DILI) in humans. Here, Park and colleagues discuss current understanding of the mechanisms mediating DILI and, through an academic–industry collaboration, propose a roadmap for the development of predictive preclinical models of human DILI.