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

Autor: Battista C; DILIsym Services division, Simulations Plus, Inc., Durham, North Carolina, USA., Shoda LKM; DILIsym Services division, Simulations Plus, Inc., Durham, North Carolina, USA., Watkins PB; Eshelman School of Pharmacy, Institute for Drug Safety Sciences, University of North Carolina, Chapel Hill, North Carolina, USA., Groettrup-Wolfers E; Pharmaceuticals Division, Pharmacovigilance, Bayer AG, Berlin, Germany., Rottmann A; Pharmaceuticals Division, Research & Early Development, Bayer AG, Berlin, Germany., Raschke M; Pharmaceuticals Division, Research & Early Development, Bayer AG, Berlin, Germany., Generaux GT; Bristol Myers Squibb, Princeton, New Jersey, USA.
Jazyk: angličtina
Zdroj: Clinical pharmacology and therapeutics [Clin Pharmacol Ther] 2023 Nov; Vol. 114 (5), pp. 1023-1032. Date of Electronic Publication: 2023 Aug 10.
DOI: 10.1002/cpt.3010
Abstrakt: 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 K p 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.
(© 2023 Simulations Plus. Clinical Pharmacology & Therapeutics © 2023 American Society for Clinical Pharmacology and Therapeutics.)
Databáze: MEDLINE
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