Volume 114, Issue 5 p. 1023-1032
Article

Quantitative Systems Toxicology Identifies Independent Mechanisms for Hepatotoxicity and Bilirubin Elevations Due to AKR1C3 Inhibitor BAY1128688

Christina Battista

Corresponding Author

Christina Battista

DILIsym Services division, Simulations Plus, Inc., Durham, North Carolina, USA

Correspondence: Christina Battista ([email protected])

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Lisl K.M. Shoda

Lisl K.M. Shoda

DILIsym Services division, Simulations Plus, Inc., Durham, North Carolina, USA

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Paul B. Watkins

Paul B. Watkins

Eshelman School of Pharmacy, Institute for Drug Safety Sciences, University of North Carolina, Chapel Hill, North Carolina, USA

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Esther Groettrup-Wolfers

Esther Groettrup-Wolfers

Pharmaceuticals Division, Pharmacovigilance, Bayer AG, Berlin, Germany

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Antje Rottmann

Antje Rottmann

Pharmaceuticals Division, Research & Early Development, Bayer AG, Berlin, Germany

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Marian Raschke

Marian Raschke

Pharmaceuticals Division, Research & Early Development, Bayer AG, Berlin, Germany

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Grant T. Generaux

Grant T. Generaux

Bristol Myers Squibb, Princeton, New Jersey, USA

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First published: 28 July 2023
Citations: 2

Abstract

BAY1128688 is a selective inhibitor of AKR1C3, investigated recently in a trial that was prematurely terminated due to drug-induced liver injury. These unexpected observations prompted use of the quantitative systems toxicology model, DILIsym, to determine possible mechanisms of hepatotoxicity. Using mechanistic in vitro toxicity data as well as clinical exposure data, DILIsym predicted the potential for BAY1128688 to cause liver toxicity (elevations in serum alanine aminotransferase (ALT)) and elevations in serum bilirubin. Initial simulations overpredicted hepatotoxicity and bilirubin elevations, so the BAY1128688 representation within DILIsym underwent optimization. The liver partition coefficient Kp was altered to align simulated bilirubin elevations with those observed clinically. Altering the mode of bile acid canalicular and basolateral efflux inhibition was necessary to accurately predict ALT elevations. Optimization results support that bilirubin elevations observed early during treatment are due to altered bilirubin metabolism and transporter inhibition, which is independent of liver injury. The modeling further supports that on-treatment ALT elevations result from inhibition of bile acid transporters, particularly the bile salt excretory pump, leading to accumulation of toxic bile acids. The predicted dose-dependent intrinsic hepatotoxicity may increase patient susceptibility to an adaptive immune response, accounting for ALT elevations observed after completion of treatment. These BAY1128688 simulations provide insight into the mechanisms behind hepatotoxicity and bilirubin elevations and may inform the potential risk posed by future compounds.

CONFLICTS OF INTEREST

C.B. and L.K.M.S. are employees of DILIsym Services (Durham, NC). E.G.-W., A.R., and M.R. are employees of Bayer AG, Berlin, Germany. G.T.G. was an employee of DILIsym Services at the time of this work and is a current employee of Bristol Myers Squibb, Princeton, NJ, USA. P.B.W. has served as a consultant to Bayer AG and serves as chair of the Scientific Advisory Board for the DILI-sim Initiative that is the producer of the DILIsym software (Simulations Plus, Durham, NC). He was not compensated for his contribution to this manuscript which was considered outside his university duties.