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Review ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.01093

Comprehensive evaluation of current organotypic and microphysiological liver models for prediction of drug-induced liver injury

  • 1Karolinska Institute (KI), Sweden

Drug induced liver injury (DILI) is a major concern for the pharmaceutical industry and constitutes one of the most important reasons for the termination of promising drug development projects. Reliable prediction of DILI liability in preclinical stages is difficult, as current experimental model systems do not accurately reflect the molecular phenotype and functionality of the human liver. As a result, multiple drugs that passed preclinical safety evaluations failed due to liver toxicity in clinical trials or postmarketing stages in recent years. To improve the selection of molecules that are taken forward into the clinics, the development of more predictive in vitro systems that enable high-throughput screening of hepatotoxic liabilities and allow for investigative studies into DILI mechanisms has gained growing interest. Specifically, it became increasingly clear that the choice of cell types and culture method both constitute important parameters that affect the predictive power of test systems. In this review, we present current 3D culture paradigms for hepatotoxicity tests and critically evaluate their utility and performance for DILI prediction. In addition, we highlight possibilities of these emerging platforms for mechanistic evaluations of selected drug candidates and present current research directions towards the further improvement of preclinical liver safety tests. We conclude that organotypic and microphysiological liver systems have provided an important step towards more reliable DILI prediction. Furthermore, we expect that the increasing availability of comprehensive benchmarking studies will facilitate model dissemination that might eventually result in their regulatory acceptance.

Keywords: Hepatotoxicity, 3D cell culture, spheroids, Liver-on-a-chip, Bioreactors, Bioprinting, MPCC

Received: 22 May 2019; Accepted: 26 Aug 2019.

Copyright: © 2019 Zhou, Shen and Lauschke. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Volker M. Lauschke, Karolinska Institute (KI), Solna, 171 77, Stockholm, Sweden, volker.lauschke@ki.se