Characterization of Fasiglifam-Related Liver Toxicity in Dogs.

Abstract

Fasiglifam, a potent and highly selective agonist of G protein-coupled receptor 40, was developed for the treatment of type 2 diabetes mellitus. However, phase III clinical programs were terminated owing to liver safety concerns. Fasiglifam-related liver toxicity was also observed in repeat-dose dog toxicology studies, characterized by granulomatous inflammation with crystal formation in the liver and/or bile ducts. These histopathological changes were not observed in rat toxicology studies. Matrix-assisted laser desorption/ionization time-of-flight mass spectrometry analysis of dog liver sections obtained from a repeat-dose toxicology study indicated that the crystalline material in the affected dog liver contained fasiglifam and fasiglifam glucuronide (fasiglifam-G). Nonclinical mechanistic studies indicated that after 14 days of repeated oral dosing with [14C]fasiglifam at 200 mg/kg per day to dogs, the concentrations of fasiglifam and fasiglifam-G in the bile exceeded the solubility limit of these compounds in the bile (approximately 3000 µg/ml). After single oral 2- and 200-mg/kg doses administered to rats and dogs, fasiglifam and fasiglifam-G concentrations in dog bile were 5- to 10-fold higher than those in rat bile for the same dose of fasiglifam, while the bile flow rate adjusted by body weight was 4- to 8-fold lower in dogs than in rats. High fasiglifam and fasiglifam-G concentrations in dog bile together with lower bile flow rate could cause crystal formation in dog bile, resulting in secondary granulomatous inflammation in the dog liver.

• Authors: Akifumi Kogame, Yuu Moriya, Ikuo Mori, Liping Pan, Akio Morohashi, Takuya Ebihara, Hideo Fukui, Yoshihiko Tagawa, Leslie Z Benet
• Journal: Drug metabolism and disposition: the biological fate of chemicals (Drug Metab Dispos) Vol. 47 Issue 5 Pg. 525-534 (05 2019) ISSN: 1521-009X [Electronic] United States
• PMID: 30765394 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.

Chemical References

• Benzofurans
• Sulfones
• TAK-875

Topics

• Animals
• Benzofurans (adverse effects, metabolism)
• Bile (metabolism)
• Chemical and Drug Induced Liver Injury (etiology)
• Dogs
• Liver (drug effects, metabolism)
• Male
• Rats
• Rats, Sprague-Dawley
• Sulfones (adverse effects, metabolism)