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Interpretation, Integration, and Implementation of In Vitro Assay Data: The Predictive Toxicity Challenge

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Drug-Induced Liver Toxicity

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

Abstract

Human drug-induced liver injury (DILI) is still a leading cause of attrition in drug development and for adverse outcomes in the marketplace. Identifying DILI risk for humans in standard animal safety testing conducted before clinical trials, in advance of the drug regulatory review and approval process is sometimes elusive. Numerous mechanisms of small molecule driven hepatotoxicity have been elucidated (e.g., reactive metabolite formation, oxidative stress, mitochondrial inhibition, bile salt export pump inhibition) and are amenable to high-throughput screening approaches. It is possible to highlight and distinguish hazard gradations of risk for human DILI when these assays are consolidated into a single point of view. In some instances, these in vitro assays highlight the potential clinical hazard without animal safety studies confirming this view. Scientifically, the idea of developing a hazard matrix approach as a better option to animal studies requires a paradigm shift that challenges the status quo. Altering opinions and traditions to effect enduring change in this area require organizational effort and commitment. Utilizing a flexible, business-disciplined framework such as Accelerating Implementation Methodology (AIM), offers structure to implement organizational change. Common barriers associated with bringing lasting change are: inappropriate sponsorship (e.g., level, commitment, and influence), organizational commitment, lack of understanding of organizational culture, resistance to change, and not identifying key stakeholders, or not hearing stakeholders’ opposing views. Given time and appropriate scientific evidence, a hazard matrix approach to identifying compounds with higher potential to cause severe DILI in the clinic can be institutionalized within the pharmaceutical industry.

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Authors and Affiliations

  1. Drug Safety Research and Development, Investigative Toxicology, Pfizer Inc., Groton, CT, USA

    Deborah S. Light & Michael D. Aleo

  2. Bioxydyn, Manchester Science Park, Manchester, UK

    J. Gerry Kenna

  3. Safer Medicines Trust, Kingsbridge, UK

    J. Gerry Kenna

Authors
  1. Deborah S. Light
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  2. Michael D. Aleo
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  3. J. Gerry Kenna
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Correspondence to J. Gerry Kenna .

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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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Light, D.S., Aleo, M.D., Kenna, J.G. (2018). Interpretation, Integration, and Implementation of In Vitro Assay Data: The Predictive Toxicity Challenge. 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_17

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  • DOI: https://doi.org/10.1007/978-1-4939-7677-5_17

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