Investigating the Potential Hepatotoxicity of ORM-48824 in a Quantitative Systems Toxicology Platform for Liver Safety, DILIsym®

Authors: Bhargava P, Tallapaka SB, Korjamo T, Howell BA, Malinen M, Oinonen T
Conference: SOT
Keywords: DILIsym, hepatoxicity, liver safety, MITOsym, QST, Quantitative Systems Toxicology (QST)
Software: DILIsym®, MITOsym®
Division: DILIsym Services

Introduction

ORM-48824 is a transient receptor potential Ankyrin-1 (TRPA1) antagonist and was initially being developed for patients with diabetic neuropathic pain, osteoarthritis, and other pathophysiological conditions to attenuate pain hypersensitivity. In vitro experiments suggested that ORM-48824 may inhibit bile acid transporters and induce mitochondrial dysfunction and oxidative stress, mechanisms that contribute to liver toxicity. DILIsym was utilized to prospectively predict clinical liver toxicity and the dominant toxicity mechanism potentially responsible for any signals predicted.

Methods

  • HepG2 cells were treated with doses of ORM-48824 ranging from 2 to 100 μμM and mitochondrial respiration was measured using a Seahorse XFe96 Analyzer
  • Reactive oxygen species (ROS) production was measured using high content screening to quantify dihydroethidium staining following ORM-48824 exposure (0.4-200 μμM)
  • ORM-48824 was administered in human ATP-binding cassette (ABC) efflux (BSEP, MRP3, and MRP4) transporters and in human solute carrier (uptake) transporter NTCP, where the accumulation of a probe substrate was measured.
  • A PBPK model was built in GastroPlus 9.8.2® for ORM-48824 and variables with known dependency on species, gender, age, height, weight, or BMI had distributions defined by the built-in Population Estimates for Age-Related Physiology (PEAR Physiology) generator
  • MITOsym® was used to parameterize ETC inhibition to in vitro mitochondrial respiration studies of ORM-48824 and ROS parameterization was performed in DILIsym
  • Doses of 500 mg BID, 250 mg BID, 100 mg BID, and 50 mg BID were simulated for 12 weeks in the NHV SimPops (N=285)
  • Mechanistic analysis was conducted by simulating 250 mg BID in a SimCohorts of 32 individuals

Conclusion

  • DILIsym is comprised of submodels that interact with one another to predict liver injury outcomes. DILIsym combines data from in vitro toxicity studies for ORM-48824, predictions exposure from GastroPlus for ORM-48824, as well as inner workings of liver physiology to predict the potential for ORM-48824 to induce liver injury or cause liver toxicity
  • In vitro studies showed that ORM-48824 induces mitochondrial dysfunction, elevation of ROS, and bile acid inhibition
  • Simulating 50 mg BID, 100 mg BID, 250 mg BID, and 500 mg BID for 12 weeks in in the NHV SimPops in DILIsym showed dose-dependent toxicity
  • No ALT elevations were predicted with 50 mg BID for 12 weeks
  • Mechanistic analysis showed that the number of individuals with ALT elevations decrease significantly when the mitochondrial dysfunction mechanism is turned off, suggesting this is the dominant toxicity pathway
  • Due to these results and other data gathered by Orion Corporation, ORM-48824 was discontinued due to potential liver toxicity, aiding in drug discovery and liver safety

By Pallavi Bhargava, Shailendra Tallapaka, Timo Korjamo, Melina Malinen, Teija Oinonen, and Brett A. Howell

2024 SOT Annual Meeting and ToxExpo, March 10–14, 2024, Salt Lake City, Utah