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Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro
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Human Liver Microphysiological System for Assessing Drug-Induced Liver Toxicity In Vitro

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

Christina Battista1, Lisl K M Shoda1, Paul B Watkins2

  • 1DILIsym Services division, Simulations Plus, Inc., Durham, North Carolina, USA.

Clinical Pharmacology and Therapeutics
|July 28, 2023
PubMed

Insights

BAY1128688, an AKR1C3 inhibitor, caused liver injury. Quantitative systems toxicology modeling revealed that bilirubin elevations stem from altered metabolism and transporter inhibition, while ALT elevations result from bile acid transporter inhibition.

Area of Science:

  • Pharmacology and Toxicology
  • Computational Biology
  • Drug Development

Background:

  • BAY1128688, a selective AKR1C3 inhibitor, was investigated in a clinical trial.
  • The trial was prematurely terminated due to observed drug-induced liver injury (DILI).
  • Understanding the mechanisms of hepatotoxicity is crucial for future drug development.

Purpose of the Study:

  • To elucidate the mechanisms of BAY1128688-induced hepatotoxicity and hyperbilirubinemia.
  • To utilize the quantitative systems toxicology (QST) model, DILIsym, for mechanistic prediction.
  • To optimize the model representation of BAY1128688 for accurate simulation of clinical observations.

Main Methods:

  • Mechanistic in vitro toxicity data and clinical exposure data were integrated into DILIsym.
  • The DILIsym model for BAY1128688 was optimized by adjusting parameters like liver partition coefficient (Kp).
  • Simulations were performed to predict serum alanine aminotransferase (ALT) and bilirubin elevations.

Main Results:

  • Initial simulations overpredicted hepatotoxicity and bilirubin elevations.
  • Optimization of Kp aligned simulated bilirubin elevations with clinical data.
  • Adjusting bile acid efflux inhibition accurately predicted ALT elevations.
  • Early bilirubin elevations are linked to altered metabolism and transporter inhibition, independent of liver injury.
  • On-treatment ALT elevations are attributed to bile acid transporter inhibition, leading to toxic bile acid accumulation.
  • Predicted dose-dependent hepatotoxicity may contribute to immune-mediated ALT elevations post-treatment.

Conclusions:

  • DILIsym simulations provide mechanistic insights into BAY1128688-induced hepatotoxicity and hyperbilirubinemia.
  • Bilirubin elevations are primarily due to altered metabolism and transporter inhibition.
  • ALT elevations are driven by bile acid transporter inhibition and potential immune responses.
  • These findings can inform risk assessment for future AKR1C3 inhibitors and other compounds.

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