Quantitative Systems Toxicology (QST) Modeling Using a New Virtual Population in BIOLOGXsym Offers Mechanistic Insights Into Bile Acid-mediated Biologics-induced Liver Injury (BILI) Upon Cimaglermin Alfa (GGF2) Administration

Authors: Beaudoin J, Vernetti L, Taylor DL, Gough A, Clemens L, Battista C, Siler SQ, Shoda LKM, Howell BA, Yang K
Conference: American College of Toxicology (ACT)
Keywords: ACT 2023, alanine aminotransferase (ALT), BILI, BIOLOGXsym, GGF2, hepatotoxicity, Quantitative Systems Toxicology (QST)
Software: BIOLOGXsym
Division: Quantitative Systems Pharmacology (QSP)

Introduction

Biopharmaceuticals are increasingly used to treat various medical conditions, but BILI events can end the clinical development of otherwise promising therapies, such as the treatment of heart failure patients with the growth factor protein GGF2. Transient increases in the BILI biomarkers plasma alanine aminotransferase (ALT) and total bilirubin (TB) suspended phase I trials of GGF2, but the mechanism underlying these biomarker elevations was not understood¹,². Combining assay outputs from a human biomimetic liver acinus microphysiology system with BIOLOGXsym, a QST modeling platform for macromolecules, representing relevant liver biochemistry and mechanistic effects of biologics on liver pathophysiology, has recently provided mechanistic understanding of GGF2-induced hepatotoxicity³, and this approach was further investigated in the present work.

Rationale and Objective

Previously performed proof-of-concept simulations of intravenously administered GGF2 (1.5 mg/kg) suggested that downregulation of basolateral bile acid transport was the main contributor to plasma ALT elevations in a representative virtual subject in BIOLOGXsym, with a minor role for biliary efflux³. It is unclear what the impact of GGF2 is on these pathways at the population level. To obtain new mechanistic insights into bile acid-mediated BILI upon GGF2 administration, an extended bile acid homeostasis representation⁴ and a new virtual population with interindividual variability in mechanistic pathways were implemented in BIOLOGXsym simulations. The differential contributions of basolateral (e.g., multidrug resistance-associated protein (MRP) 3/4-mediated) versus biliary (e.g., bile salt export pump (BSEP)-mediated) bile acid efflux pathways were investigated in a representative virtual subject, and in a new cohort of individuals (n=32) that were deemed sensitive to GGF2 hepatotoxicity.

Conclusions

  • In vitro data from LAMPS can be successfully integrated into a QST model to recapitulate BILI liabilities and provide mechanistic explanation for observed clinical liver safety signals.
  • Simulations with a representative virtual subject in BIOLOGXsym using an extended bile acid representation continue to support a key role for basolateral bile acid transport downregulation in explaining GGF2-induced ALT elevations.
  • However, a more dominant role for the downregulation of biliary bile acid excretion, and subsequent hepatocellular BA accumulation, is predicted at the population level in sensitive individuals.
  • In conclusion, population-based simulations in BIOLOGXsym can provide new mechanistic insights into BILI.

References

  1. Lenihan et al. JACC Basic Transl Sci. 2016 Dec;1(7).
  2. Longo et al. Clin Pharmacol Ther. 2017 Dec;102(6).
  3. Beaudoin et al. Int J Mol Sci. 2023 Jun;24(11).
  4. Beaudoin et al. Front Pharmacol. 2023 Jan;13.
  5. Lee-Montiel et al. Exp Biol Med (Maywood). 2017 Oct;242(16).
  6. Mosedale et al. Toxicol Sci. 2018 Feb;161(2).

Acknowledgements

This work was funded by the National Institute of Health (NIH) R44TR003535.

By James J. Beaudoin, Lawrence A. Vernetti, D. Lansing Taylor, Albert Gough, Lara Clemens, Christina Battista, Scott Q. Siler, Lisl K.M. Shoda, Brett A. Howell and Kyunghee Yang

American College of Toxicology (ACT) 2023, Orlando, Florida, November 12-15, 2023