Cited by 75Drug-Induced Hepatotoxicity and ProtectionAnimal testing and alternativesComputational Drug Discovery Methods

Linking physiology to toxicity using DILIsym®, a mechanistic mathematical model of drug‐induced liver injury

Shoda, Lisl K. M., Woodhead, Jeffrey L., Siler, Scott Q., Watkins, Paul B., Howell, Brett A.·2014·Biopharmaceutics & Drug Disposition

Abstract

The drug development industry faces multiple challenges in the realization of safe effective drugs. Computational modeling approaches can be used to support these efforts. One approach, mechanistic modeling, is new to the realm of drug safety. It holds the promise of not only predicting toxicity for novel compounds, but also illuminating the mechanistic underpinnings of toxicity. To increase the scientific community's familiarity with mechanistic modeling in drug safety, this article seeks to provide perspective on the type of data used, how they are used and where they are lacking. Examples are derived from the development of DILIsym® software, a mechanistic model of drug‐induced liver injury (DILI). DILIsym® simulates the mechanistic interactions and events from compound administration through the progression of liver injury and regeneration. Modeling mitochondrial toxicity illustrates the type and use of in vitro data to represent biological interactions, as well as insights on key differences between in vitro and in vivo conditions. Modeling bile acid toxicity illustrates a case in which the over‐arching mechanism is well accepted, but many mechanistic details are lacking. Modeling was used to identify measurements predicted to strongly impact toxicity. Finally, modeling innate immune responses illustrates the importance of time‐series data, particularly in the presence of positive and negative feedback loops, as well as the need for data from different animal species for better translation. These concepts are germane to most mechanistic models, although the details will vary. The use of mechanistic models is expected to improve the rational design of new drugs. Copyright © 2013 John Wiley & Sons, Ltd.

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Crossref · 10.1002/bdd.1878

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121 of 121 references verified0 citation errors · 0 not checkable

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  • Consortiums have been established to develop more comprehensive tissue- and disease-focused models, such as DILIsym (drug-induced liver injury), Certara's QSP Immunogenicity Consortium, and the Critical Path for Alzheimer's Disease.

    “Consortiums have also been established to develop more comprehensive tissue‐ and disease‐focused models, such as DILIsym27 (drug‐induced liver injury), Certara's QSP Immunogenicity Consortium, or the Critical Path for Alzheimer's Disease; hence, these may serve in specific cases.”

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Authors
Shoda, L. K. M., Woodhead, J. L., Siler, S. Q., Watkins, P. B., & Howell, B. A.
Affiliations
The Hamner Institutes for Health Sciences (US)
Corresponding author
Howell, Brett A.
Venue
Biopharmaceutics & Drug Disposition
Publisher
Wiley
Published
2013-11-25
Volume
35
Issue
1
Pages
33-49
ISSN
  • 0142-2782 (ISSN-L)
  • 1099-081X
OpenAlex
W1609658954
Cited by
75
References
121
Citations by year
2026: 3 · 2025: 5 · 2024: 4 · 2023: 4 · 2022: 5 · 2021: 3 · 2020: 6 · 2019: 10 · 2018: 5 · 2017: 9 · 2016: 11 · 2015: 4 · 2014: 6
FWCI
1.14
Type
journal article
Language
en
Open access
closed
Locations
  • Biopharmaceutics & Drug Disposition (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
  • Health Sciences › Veterinary › Small Animals › Animal testing and alternatives
  • Physical Sciences › Computer Science › Computational Theory and Mathematics › Computational Drug Discovery Methods
Keywords
drug-induced liver injury, drug safety, mitochondrial toxicity, bile acid toxicity, innate immune response, liver regeneration, in vitro to in vivo translation, time series, positive and negative feedback loops, species differences, toxicity prediction
MeSH terms
Animals, Bile Acids and Salts, Humans, Immunity, Innate, Mitochondria, Models, Biological, Software, Chemical and Drug Induced Liver Injury

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