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Drug-Induced Liver Toxicity pp 101–121Cite as

An Introduction to DILIsym® Software, a Mechanistic Mathematical Representation of Drug-Induced Liver Injury

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

Abstract

Drug-induced liver injury (DILI) is one of the primary reasons why a new drug candidate may fail during development. To address this challenge, a mathematical representation, DILIsym®, has been developed as a result of an ongoing public-private partnership involving scientists from industry, academia, and the FDA. DILIsym employs mathematical representations of mechanistic interactions and events from drug administration through the progression of liver injury and regeneration to the release of traditional and novel serum biomarkers. The model parameters are varied to recreate population variation in DILI susceptibility. Using in vitro data to represent potential mitochondrial dysfunction, bile acid transporter inhibition, and/or reactive oxygen species generation, DILIsym has been able to predict the in vivo liver safety profile in individuals and in simulated populations for a growing list of drugs. DILIsym is being increasingly used to assist in decision making throughout the development pipeline, from predicting interspecies differences and their hepatotoxicity potential to aiding in the design of dosing regimens to minimize hepatotoxicity when this liability is identified. Furthermore, DILIsym’s incorporation of the release and clearance kinetics of traditional and emerging serum biomarkers can improve interpretation of potential liver safety signals. This chapter outlines the interactions and toxicity mechanisms included in DILIsym and the process of representing a compound in the software. Examples of toxicity profile predictions and biomarker interpretations are included along with future directions for the software.

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Authors and Affiliations

  1. Institute for Drug Safety Sciences, Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, NC, USA

    Christina Battista & Paul B. Watkins

  2. DILIsym Services, Inc., Research Triangle Park, NC, USA

    Christina Battista, Brett A. Howell, Scott Q. Siler & Paul B. Watkins

Authors
  1. Christina Battista
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  2. Brett A. Howell
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  3. Scott Q. Siler
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  4. Paul B. Watkins
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Corresponding author

Correspondence to Paul B. Watkins .

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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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Battista, C., Howell, B.A., Siler, S.Q., Watkins, P.B. (2018). An Introduction to DILIsym® Software, a Mechanistic Mathematical Representation of Drug-Induced Liver Injury. 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_6

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