Control Compounds for Preclinical Drug-Induced Liver Injury Assessment: Consensus-driven systematic review by the ProEuroDILI Network-Reference-Cited by-同舟云学术

Control Compounds for Preclinical Drug-Induced Liver Injury Assessment: Consensus-driven systematic review by the ProEuroDILI Network

Published:2023-11-09 Issue: Volume: Page:
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Author:

Segovia-Zafra Antonio¹,Villanueva-Paz Marina¹^ORCID,Serras Ana Sofia²,Matilla-Cabello Gonzalo³,Bodoque-García Ana³,Zeo-Sánchez Daniel Enrique Di³,Niu Hao³,Álvarez-Álvarez Ismael¹,Sanz-Villanueva Laura⁴,Godec Sergej⁵,Milisav Irina⁶,Andrade Raúl J¹,Lucena María Isabel¹,Checa José Carlos Fernández⁷,Cubero Francisco Javier⁸,Miranda Joana²,Nelson Leonard⁹

Affiliation:

1. Servicios de Aparato Digestivo y Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Universidad de Málaga, Málaga, Spain. 2 Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.

2. Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.

3. Servicios de Aparato Digestivo y Farmacología Clínica, Hospital Universitario Virgen de la Victoria, Instituto de Investigación Biomédica de Málaga y Plataforma en Nanomedicina-IBIMA Plataforma BIONAND, Universidad de Málaga, Málaga, Spain.

4. Immunology and Diabetes Unit, St Vincent's Institute, Fitzroy VIC, Australia. Department of Medicine, St Vincent's Hospital, University of Melbourne, Fitzroy, VIC, Australia.

5. Clinical Department of Anaesthesiology and Intensive Therapy, University Medical Center, Ljubljana, Slovenia; Faculty of Medicine, Institute of Pathophysiology, University of Ljubljana, Zaloska 4, 1000 Ljubljana, Slovenia

6. Faculty of Medicine, Institute of Pathophysiology, University of Ljubljana, Zaloska 4, SI-1000 Ljubljana, Slovenia; Faculty of Health Sciences, University of Ljubljana, Zdravstvena pot 5, 1000 Ljubljana, Slovenia

7. Centro de Investigación Biomédica en Red Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain. Department of Cell Death and Proliferation, Institute of Biomedical Research of Barcelona (IIBB), CSIC, Barcelona, Spain. Liver Unit, Hospital Clinic I Provincial de Barcelona, Barcelona, Spain. Instituto de Investigaciones Biomédicas August Pi i Sunyer (IDIBAPS), Barcelona, Spain. Department of Medicine, Keck School of Division of Gastrointestinal and Liver disease, University of Southern California, Lo

8. Department of Immunology, Ophthalmology and ORL, Complutense University School of Medicine, Madrid, Spain.

9. Institute for Bioengineering, School of Engineering, Faraday Building, The University of Edinburgh, Scotland, United Kingdom.

Abstract

Abstract Idiosyncratic drug-induced liver injury (DILI) is a complex and unpredictable event caused by different drugs, herbal, and dietary supplements. The early identification of human hepatotoxicity at the preclinical stages remains a major challenge, in which the selection of validated in vitro systems and test drugs has a significant impact. This systematic review aims to analyse the compounds used in hepatotoxicity assays and establish a unified list of DILI positive and negative control drugs for validation of in vitro models of DILI, supported by literature and clinical evidence and endorsed by a committee of experts from the COST Action ProEuroDILI Network (CA 17112). This systematic review was performed in accordance with the 2020 PRISMA guidelines. Original research articles focused on investigating DILI occurrence using in vitro human models performing at least one hepatotoxicity assay with positive and negative control compounds were included. A modified version of the "Toxicological Data Reliability Assessment Tool" (ToxRTool) was used to assess the bias of the included studies. A total of 2,936 studies were retrieved from the different databases. Of these, 51 met the inclusion criteria, with 30 categorized as reliable without restrictions. Diclofenac and buspirone were the most commonly used DILI-positive and DILI-negative control drugs, respectively. Although there was a broad consensus on the positive compounds, the selection of negative control compounds remained less clear. Regarding the models used, the 2D monoculture of primary human hepatocytes (PHHs) was the favoured choice. However, there was no clear consensus on the drug concentrations. Short acute exposure times were mostly utilised, and cytotoxicity was the preferred endpoint. The extensive analysis of included studies highlighted the lack of agreement on appropriate control compounds for the in vitro assessment of DILI. Therefore, following comprehensive in vitro and clinical data analysis together with input from the expert committee, an evidence-based consensus-driven list of 10 positive and negative drugs is proposed for validating new in vitro models for improving preclinical drug safety testing regimes.

Publisher

Research Square Platform LLC

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