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Toxicol Sci. 2018 Nov 1;166(1):123-130. doi: 10.1093/toxsci/kfy191.

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

Author information

1
DILIsym Services, Inc., Research Triangle Park, North Carolina.
2
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.
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
DILIsym Services, Inc., Six Davis Drive, PO BOX 12317, Research Triangle Park, NC 27709.

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.

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