Quantitative Systems Toxicology Identifies Independent Mechanisms for Hepatotoxicity and Bilirubin Elevations Due to AKR1C3 Inhibitor BAY1128688
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Le résumé fourni par la source
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.
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Le contrôle bibliographique ouvert
DOI retrouvé dans Crossref DOI retrouvé, mais le titre doit être comparé manuellement.
- Titre Crossref
- Quantitative Systems Toxicology Identifies Independent Mechanisms for Hepatotoxicity and Bilirubin Elevations Due to <scp>AKR1C3</scp> Inhibitor <scp>BAY1128688</scp>
- Date Crossref
- 10/08/2023
- Éditeur
- Wiley
- Type
- journal-article
Ce recoupement confirme des métadonnées liées au DOI. Il ne confirme ni la méthode ni les conclusions de l’étude, et il ne compte pas comme une seconde source scientifique indépendante.
Où se fait cette recherche
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Simulations Plus (United States) pays non établi dans la noticeEntreprise
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University of North Carolina at Chapel Hill pays non établi dans la noticeUniversité ou école supérieure
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Bayer (Germany) pays non établi dans la noticeEntreprise
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Bristol-Myers Squibb (United States) pays non établi dans la noticeEntreprise
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Inc. Durham North Carolina USA DILIsym Services division Simulations Plus pays non établi dans la noticeEntreprise
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Eshelman School of Pharmacy Institute for Drug Safety Sciences University of North Carolina Chapel Hill North Carolina USA pays non établi dans la noticeUniversité ou école supérieure
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Pharmaceuticals Division Pharmacovigilance Bayer AG Berlin Germany pays non établi dans la noticeInstitution
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Pharmaceuticals Division Research & pays non établi dans la noticeInstitution
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Bristol Myers Squibb Princeton New Jersey USA pays non établi dans la noticeInstitution
Simulations Plus (United States), University of North Carolina at Chapel Hill et Bayer (Germany), avec 6 autres affiliations.
Une affiliation ne permet pas de déduire la nationalité d’un auteur.