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PERSPECTIVE article

Front. Drug Discov.
Sec. Technologies and Strategies to Enable Drug Discovery
Volume 5 - 2025 | doi: 10.3389/fddsv.2025.1536756

Perspective: How complex in vitro models (CIVMs) are addressing the challenges of predicting drug induced liver injury (DILI)

Provisionally accepted
Katy Taylor Katy Taylor 1Rebecca Ram Rebecca Ram 1,2*Lorna Ewart Lorna Ewart 3Chris Goldring Chris Goldring 4Giusy Russomanno Giusy Russomanno 4Guruprasad Padur Aithal Guruprasad Padur Aithal 5Tomasz Kostrzewski Tomasz Kostrzewski 6Caroline Bauch Caroline Bauch 7John Malcolm Wilkinson John Malcolm Wilkinson 8,9Stephanie Modi Stephanie Modi 10John Gerry Kenna John Gerry Kenna 2Jarrod Bailey Jarrod Bailey 10
  • 1 Alliance for Human Relevant Science, London, United Kingdom
  • 2 Safer Medicines Trust, Kingsbridge, United Kingdom
  • 3 Emulate Inc., Boston, Massachusetts, United States
  • 4 University of Liverpool, Liverpool, North West England, United Kingdom
  • 5 University of Nottingham, Nottingham, England, United Kingdom
  • 6 CN-BIO, Cambridge, United Kingdom
  • 7 Cyprotex (United States), Kalamazoo, Michigan, United States
  • 8 Kirkstall (United Kingdom), Rotherham, United Kingdom
  • 9 The University of Sheffield, Sheffield, England, United Kingdom
  • 10 Animal Free Research UK, London, United Kingdom

The final, formatted version of the article will be published soon.

    Predicting which drugs might have the potential to cause drug-induced liver injury (DILI) is highly complex and the current methods, 2D cell-based models and animal tests, are not sensitive enough to prevent some costly failures in clinical trials or to avoid all patient safety concerns for DILI post-market. Animal-based methods are hampered by important species differences in metabolism and adaptive immunity compared to humans and the standard 2D in vitro approaches have limited metabolic functionality and complexity. On 24 April 2023 the Alliance for Human Relevant Science (https://www.humanrelevantscience.org/) hosted a workshop at the Royal Society, London entitled Drug Induced Liver Injury (DILI): Can Human-Focused Testing Improve ClinicalTranslation? The conclusion was that complex in vitro models (CIVMs) provide a significant step forward in the safety testing paradigm. This perspective article, written by the participants, builds on those discussions to provide a 'state of play' on liver CIVMs with recommendations for how to encourage their greater uptake by the pharmaceutical industry.

    Keywords: DILI, liver injury, In vitro methods, Animal testing, replacement, spheroids, Microphysiological systems, Safety testing

    Received: 29 Nov 2024; Accepted: 24 Jan 2025.

    Copyright: © 2025 Taylor, Ram, Ewart, Goldring, Russomanno, Aithal, Kostrzewski, Bauch, Wilkinson, Modi, Kenna and Bailey. 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) or licensor 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: Rebecca Ram, Safer Medicines Trust, Kingsbridge, TQ7 9AX, United Kingdom

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.