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

Christopher E Goldring (1) , André Guillouzo (2) , Philip G Hewitt (3) , Magnus Ingelman-Sundberg (4) , Klaus Gjervig Jensen , Satu Juhila , Ursula Klingmüller (5) , Gilles Labbe (6) , Michael J Liguori (7) , Cerys A Lovatt (8) , Paul Morgan (9) , Dean J Naisbitt (1) , Raymond H H Pieters (10) , Jan Snoeys (11) , Bob van de Water (12) , Dominic P Williams (9) , B Kevin Park (1) , Richard J Weaver (13) , Eric A Blomme (7) , Amy E Chadwick (1) , Ian M Copple (1) , Helga H J Gerets (14)

1 University of Liverpool
2 NuMeCan - Nutrition, Métabolismes et Cancer
3 Merck Research Laboratories
4 Karolinska Institutet [Stockholm]
5 Division Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ)
6 SANOFI Recherche
7 Abbvie Inc. [North Chicago]
8 GlaxoSmithKline
9 AstraZeneca
10 University Medical Center [Utrecht]
11 Janssen Research & Development
12 Leiden University
13 IRIS - Institut de Recherches Internationales Servier [Suresnes]
14 UCB BioPharma [Braine l’Alleud, Belgium]

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.

Keywords: Adverse effects; Drug discovery; Preclinical research

Domains: Life Sciences [q-bio]; Life Sciences [q-bio]; Human health and pathology; Hépatology and Gastroenterology

Christopher E Goldring, André Guillouzo, Philip G Hewitt, Magnus Ingelman-Sundberg, Klaus Gjervig Jensen, et al.. Managing the challenge of drug-induced liver injury a roadmap for the development and deployment of preclinical predictive models. Nature Reviews Drug Discovery, 2020, 19 (2), pp.131-148. ⟨10.1038/s41573-019-0048-x⟩. ⟨hal-02397617⟩