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Prediction of Human Liver Toxicity Using In Vitro Assays: Limitations and Opportunities

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Drug-Induced Liver Toxicity

Part of the book series: Methods in Pharmacology and Toxicology ((MIPT))

Abstract

This chapter provides a short review of the current challenges to predict the risk for drug-induced liver injury (DILI) in humans using in vitro assays. Simple single cell-type in vitro cytotoxicity assays may fail to predict complex in vivo interconnected mechanism-based toxicities. Additionally, the lack of standardization of in vitro assays complicates data interpretation and makes assay comparison difficult. The selection of a given assay may depend on the DILI mechanism to be explored, short-term versus long-term culture, and the ability to study the toxicity of parent compounds or metabolites. Indeed, a single model is unlikely to address all the relevant mechanisms that can lead to liver toxicity. A better implementation of preclinical data as well as harmonization of current, emerging and novel in vitro systems should help to better predict human DILI. Case studies are also provided to illustrate how the in vitro assays can help to derisk preclinical in vivo toxicity findings and to better predict clinical human liver toxicity outcomes. Opportunities in the DILI field are also discussed, in particular the need to use more relevant in vitro models to better mimic the in vivo situation (e.g., pathological state, long term exposure, integration of inflammatory components), as well as the access to in vitro models from multiple species. Finally the use of relevant technologies (e.g., label free approach), in silico approaches integrating data from new chemical spaces, and the setting up of a preclinical DILI guidance from the scientific community and authorities are also important steps which should help the scientific community to improve DILI prediction.

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Authors and Affiliations

  1. Non-Clinical Development, Investigative Toxicology Group, UCB BioPharma SPRL, Braine-l’Alleud, Belgium

    Franck A. Atienzar

  2. Non-Clinical Development, Development DMPK/PKPD, UCB BioPharma SPRL, Braine-l’Alleud, Belgium

    Jean-Marie Nicolas

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  1. Franck A. Atienzar
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  2. Jean-Marie Nicolas
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Correspondence to Franck A. Atienzar .

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Editors and Affiliations

  1. Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA

    Minjun Chen

  2. Drug Safety Research and Development, Pfizer Inc., Groton, CT, USA

    Yvonne Will

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Atienzar, F.A., Nicolas, JM. (2018). Prediction of Human Liver Toxicity Using In Vitro Assays: Limitations and Opportunities. In: Chen, M., Will, Y. (eds) Drug-Induced Liver Toxicity. Methods in Pharmacology and Toxicology. Humana, New York, NY. https://doi.org/10.1007/978-1-4939-7677-5_7

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