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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 [ 14 C]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 µ g/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., (Copyright © 2019 by The American Society for Pharmacology and Experimental Therapeutics.)

Fasiglifam (TAK-875), a Free Fatty Acid Receptor 1 (FFAR1) agonist in development for the treatment of type 2 diabetes, was voluntarily terminated in phase 3 due to adverse liver effects. A mechanistic investigation described in this manuscript focused on the inhibition of bile acid (BA) transporters as a driver of the liver findings. TAK-875 was an in vitro inhibitor of multiple influx (NTCP and OATPs) and efflux (BSEP and MRPs) hepatobiliary BA transporters at micromolar concentrations. Repeat dose studies determined that TAK-875 caused a dose-dependent increase in serum total BA in rats and dogs. Additionally, there were dose-dependent increases in both unconjugated and conjugated individual BAs in both species. Rats had an increase in serum markers of liver injury without correlative microscopic signs of tissue damage. Two of 6 dogs that received the highest dose of TAK-875 developed liver injury with clinical pathology changes, and by microscopic analysis had portal granulomatous inflammation with neutrophils around a crystalline deposition. The BA composition of dog bile also significantly changed in a dose-dependent manner following TAK-875 administration. At the highest dose, levels of taurocholic acid were 50% greater than in controls with a corresponding 50% decrease in taurochenodeoxycholic acid. Transporter inhibition by TAK-875 may cause liver injury in dogs through altered bile BA composition characteristics, as evidenced by crystalline deposition, likely composed of test article, in the bile duct. In conclusion, a combination of in vitro and in vivo evidence suggests that BA transporter inhibition could contribute to TAK-875-mediated liver injury in dogs., (© The Author 2017. Published by Oxford University Press on behalf of the Society of Toxicology.)