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Title: Using Quantitative Systems Toxicology to Investigate Observed Species Differences in CKA-Mediated Hepatotoxicity

Abstract

CKA, a chemokine receptor antagonist intended for treating inflammatory conditions, produced dose-dependent hepatotoxicity in rats but advanced into the clinic where single doses of CKA up to 600 mg appeared safe in humans. Because existing toxicological platforms used during drug development are not perfectly predictive, a quantitative systems toxicology model investigated the hepatotoxic potential of CKA in humans and rats through in vitro assessments of CKA on mitochondrial respiration, oxidative stress, and bile acid transporters. DILIsym predicted that single doses of CKA caused serum ALT >3xULN in a subset of the simulated rat population, while single doses in a simulated human population did not produce serum ALT elevations. Species differences were largely attributed to differences in liver exposure, but increased sensitivity to inhibition of mitochondrial respiration in the rat also contributed. We conclude that mechanistic modeling can elucidate species differences in the hepatotoxic potential of drug candidates.

Authors:
ORCiD logo [1];  [2]; ORCiD logo [3];  [4];  [5];  [2];  [6]
  1. DILIsym Services, Inc., Research Triangle Park, North Carolina, Division of Pharmacotherapy and Experimental Therapeutics, UNC Institute for Drug Safety Sciences, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  2. DILIsym Services, Inc., Research Triangle Park, North Carolina
  3. Safety and ADME Translational Sciences, Drug Safety and Metabolism, IMED Biotech Unit, Astra Zeneca R&D, Cambridge CB4 0WG, UK
  4. Safety and ADME Translational Sciences, Drug Safety and Metabolism, IMED Biotech Unit, Astra Zeneca R&D, Waltham, Massachusetts
  5. Division of Pharmacotherapy and Experimental Therapeutics, UNC Institute for Drug Safety Sciences, UNC Eshelman School of Pharmacy, The University of North Carolina at Chapel Hill, Chapel Hill, North Carolina
  6. DILIsym Services, Inc., Research Triangle Park, North Carolina, DILIsym Services, Inc., Six Davis Drive, PO BOX 12317, Research Triangle Park, NC 27709
Publication Date:
Research Org.:
Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE Office of Science (SC); U.S. Food and Drug Administration (FDA)
OSTI Identifier:
1479590
Alternate Identifier(s):
OSTI ID: 1466881; OSTI ID: 1905011
Grant/Contract Number:  
SC0014664
Resource Type:
Journal Article: Published Article
Journal Name:
Toxicological Sciences
Additional Journal Information:
Journal Name: Toxicological Sciences Journal Volume: 166 Journal Issue: 1; Journal ID: ISSN 1096-6080
Publisher:
Oxford University Press
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; toxicology; drug-induced liver injury; systems pharmacology; hepatotoxicity; CKA; quantitative systems toxicology; quantitative systems pharmacology; mitochondria; membrane transport proteins; liver; rats; toxic effects

Citation Formats

Battista, Christina, Yang, Kyunghee, Stahl, Simone H., Mettetal, Jerome T., Watkins, Paul B., Siler, Scott Q., and Howell, Brett A. Using Quantitative Systems Toxicology to Investigate Observed Species Differences in CKA-Mediated Hepatotoxicity. United States: N. p., 2018. Web. doi:10.1093/toxsci/kfy191.
Battista, Christina, Yang, Kyunghee, Stahl, Simone H., Mettetal, Jerome T., Watkins, Paul B., Siler, Scott Q., & Howell, Brett A. Using Quantitative Systems Toxicology to Investigate Observed Species Differences in CKA-Mediated Hepatotoxicity. United States. https://doi.org/10.1093/toxsci/kfy191
Battista, Christina, Yang, Kyunghee, Stahl, Simone H., Mettetal, Jerome T., Watkins, Paul B., Siler, Scott Q., and Howell, Brett A. 2018. "Using Quantitative Systems Toxicology to Investigate Observed Species Differences in CKA-Mediated Hepatotoxicity". United States. https://doi.org/10.1093/toxsci/kfy191.
@article{osti_1479590,
title = {Using Quantitative Systems Toxicology to Investigate Observed Species Differences in CKA-Mediated Hepatotoxicity},
author = {Battista, Christina and Yang, Kyunghee and Stahl, Simone H. and Mettetal, Jerome T. and Watkins, Paul B. and Siler, Scott Q. and Howell, Brett A.},
abstractNote = {CKA, a chemokine receptor antagonist intended for treating inflammatory conditions, produced dose-dependent hepatotoxicity in rats but advanced into the clinic where single doses of CKA up to 600 mg appeared safe in humans. Because existing toxicological platforms used during drug development are not perfectly predictive, a quantitative systems toxicology model investigated the hepatotoxic potential of CKA in humans and rats through in vitro assessments of CKA on mitochondrial respiration, oxidative stress, and bile acid transporters. DILIsym predicted that single doses of CKA caused serum ALT >3xULN in a subset of the simulated rat population, while single doses in a simulated human population did not produce serum ALT elevations. Species differences were largely attributed to differences in liver exposure, but increased sensitivity to inhibition of mitochondrial respiration in the rat also contributed. We conclude that mechanistic modeling can elucidate species differences in the hepatotoxic potential of drug candidates.},
doi = {10.1093/toxsci/kfy191},
url = {https://www.osti.gov/biblio/1479590}, journal = {Toxicological Sciences},
issn = {1096-6080},
number = 1,
volume = 166,
place = {United States},
year = {Mon Jul 30 00:00:00 EDT 2018},
month = {Mon Jul 30 00:00:00 EDT 2018}
}

Journal Article:
Free Publicly Available Full Text
Publisher's Version of Record at https://doi.org/10.1093/toxsci/kfy191

Citation Metrics:
Cited by: 7 works
Citation information provided by
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