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Advanced preclinical models for evaluation of drug induced liver injury - consensus statement by the European Drug-Induced Liver Injury Network [Pro-Euro-DILI-Net]

Fernandez-Checa, Jose C.; Bagnaninchi, Pierre; Ye, Hui; Sancho-Bru, Pau; Falcon-Perez, Juan M.; Royo, Felix; Garcia-Ruiz, Carmen; Konu, Ozlen; Miranda, Joana; Lunov, Oleg; Dejneka, Alexandr; Elfick, Alistair; McDonald, Alison; Sullivan, Gareth J.; Aithal, Guruprasad; Lucena, M. Isabel; Andrade, Raul J.; Fromenty, Bernard; Krannendonk, Michel; Cubero, Francisco Javier; Nelson, Leonard J.

Advanced preclinical models for evaluation of drug induced liver injury - consensus statement by the European Drug-Induced Liver Injury Network [Pro-Euro-DILI-Net] Thumbnail


Authors

Jose C. Fernandez-Checa

Pierre Bagnaninchi

Hui Ye

Pau Sancho-Bru

Juan M. Falcon-Perez

Felix Royo

Carmen Garcia-Ruiz

Ozlen Konu

Joana Miranda

Oleg Lunov

Alexandr Dejneka

Alistair Elfick

Alison McDonald

Gareth J. Sullivan

M. Isabel Lucena

Raul J. Andrade

Bernard Fromenty

Michel Krannendonk

Francisco Javier Cubero

Leonard J. Nelson



Abstract

Drug induced liver injury (DILI) is a major cause of acute liver failure (ALF) and one of the leading indications for liver transplantation in Western societies. Given the wide use of both prescribed and over the counter drugs, DILI has become a major health issue with a pressing need to find novel and effective therapies. Although significant progress has been made in understanding the molecular mechanisms underlying DILI, our incomplete knowledge of its pathogenesis and inability to predict DILI is largely due to both discordance between human and animal DILI in preclinical drug development and a lack of models that faithfully recapitulate complex pathophysiological features of human DILI. This is exemplified by the hepatotoxicity of acetaminophen (APAP) overdose, a major cause ALF due to its extensive worldwide use as an analgesic. Despite intensive efforts utilizing current animal and in vitro models, the mechanisms involved in the hepatotoxicity of APAP are still not fully understood. In this expert Consensus Statement, which is endorsed by the European Drug-Induced Liver Injury Network, we aim to facilitate and outline clinically impactful knowledge discovery by detailing the requirements for more realistic human-based systems to assess hepatotoxicity to guide future drug safety testing. We present novel insights and major players in APAP pathophysiology and describe emerging in vitro and in vivo pre-clinical models, as well as advanced imaging and in silico technologies, which may improve prediction of clinical outcomes of DILI including APAP hepatotoxicity.

Citation

Fernandez-Checa, J. C., Bagnaninchi, P., Ye, H., Sancho-Bru, P., Falcon-Perez, J. M., Royo, F., …Nelson, L. J. (2021). Advanced preclinical models for evaluation of drug induced liver injury - consensus statement by the European Drug-Induced Liver Injury Network [Pro-Euro-DILI-Net]. Journal of Hepatology, 75(4), 935-959. https://doi.org/10.1016/j.jhep.2021.06.021

Journal Article Type Article
Acceptance Date Jun 11, 2021
Online Publication Date Jun 24, 2021
Publication Date 2021-10
Deposit Date Jun 26, 2021
Publicly Available Date Jul 2, 2021
Journal Journal of Hepatology
Print ISSN 0168-8278
Electronic ISSN 1600-0641
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 75
Issue 4
Pages 935-959
DOI https://doi.org/10.1016/j.jhep.2021.06.021
Keywords Hepatology
Public URL https://nottingham-repository.worktribe.com/output/5724571
Publisher URL https://www.journal-of-hepatology.eu/article/S0168-8278(21)00441-4/fulltext
Related Public URLs https://www.sciencedirect.com/science/article/pii/S0168827821004414

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