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

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

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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 (2019) doi:10.1038/s41573-019-0048-x

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