The use of in vitro ADME techniques in understanding fasiglifam-induced liver injury

Abstract

Fasiglifam (TAK-875) is a highly potent and selective GPR40 (FFAR1) agonist that was under development by Takeda for the treatment of Type II diabetes mellitus until its withdrawal in 2013 due to liver safety concerns. It acts on the b cells of the pancreas, which stimulates insulin secretion in a glucose-dependent manner and Phase II trials showed it to be effective in lowering blood sugar.

Following preclinical toxicology studies, there were no histological signs of liver injury observed in the rat (26 week study).  However, following the dog study (39 weeks plus 13 weeks recovery), hyperplasia of the bile duct was observed, with raised ALT and AST levels.  The in vivo rat and dog studies showed serum bile acid elevations preceded overt liver injury, suggesting a temporal and mechanistic relationship. A Phase III clinical study held in Japan, highlighted evidence of elevated levels of ALT and bilirubin.

The current work highlights the investigations performed, including determining if fasiglifam perturbs processes involved in bilirubin and or bile salt disposition in vitro. Some drugs (indinavir, atazanavir, rifampicin, rifamycin and probenecid) have been shown to induce hyperbilirubinaemia by perturbing one or more of the hepatocellular processes involved in bilirubin metabolism and excretion, including cholestasis (impaired bile flow).