title: Fasiglifam (TAK-875) Alters Bile Acid Homeostasis in Rats and Dogs: A Potential Cause of Drug Induced Liver Injury.
abstract: 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.
authors.affiliation: Takeda Pharmaceuticals International Co, Cambridge, Massachusetts, USA.
authors.forename: Francis S
authors.initials: FS
authors.lastname: Wolenski
authors.affiliation: Takeda Pharmaceuticals International Co, Cambridge, Massachusetts, USA.
authors.forename: Andy Z X
authors.initials: AZX
authors.lastname: Zhu
authors.affiliation: Takeda Pharmaceuticals International Co, Cambridge, Massachusetts, USA.
authors.forename: Mike
authors.initials: M
authors.lastname: Johnson
authors.affiliation: Takeda Pharmaceuticals International Co, Cambridge, Massachusetts, USA.
authors.forename: Shaoxia
authors.initials: S
authors.lastname: Yu
authors.affiliation: Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Yuu
authors.initials: Y
authors.lastname: Moriya
authors.affiliation: Takeda Pharmaceutical Company Limited, Fujisawa, Kanagawa, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Ebihara
authors.affiliation: Takeda Pharmaceuticals International Co, Cambridge, Massachusetts, USA.
authors.forename: Vilmos
authors.initials: V
authors.lastname: Csizmadia
authors.affiliation: Takeda Pharmaceuticals International Co, Cambridge, Massachusetts, USA.
authors.forename: Jessica
authors.initials: J
authors.lastname: Grieves
authors.affiliation: Takeda Pharmaceuticals International Co, Cambridge, Massachusetts, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Paton
authors.affiliation: Takeda Pharmaceuticals International Co, Cambridge, Massachusetts, USA.
authors.forename: Mingxiang
authors.initials: M
authors.lastname: Liao
authors.affiliation: Takeda Pharmaceuticals International Co, Cambridge, Massachusetts, USA.
authors.forename: Christopher
authors.initials: C
authors.lastname: Gemski
authors.affiliation: Takeda Pharmaceuticals International Co, Deerfield, Illinois, USA.
authors.forename: Liping
authors.initials: L
authors.lastname: Pan
authors.affiliation: Takeda Pharmaceuticals International Co, Deerfield, Illinois, USA.
authors.forename: Majid
authors.initials: M
authors.lastname: Vakilynejad
authors.affiliation: Takeda Pharmaceuticals International Co, Cambridge, Massachusetts, USA.
authors.forename: Yvonne P
authors.initials: YP
authors.lastname: Dragan
authors.affiliation: Takeda Pharmaceuticals International Co, Cambridge, Massachusetts, USA.
authors.forename: Swapan K
authors.initials: SK
authors.lastname: Chowdhury
authors.affiliation: Takeda Pharmaceuticals International Co, Cambridge, Massachusetts, USA.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Kirby
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001572:Benzofurans / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*; D001647:Bile Acids and Salts / Q000378:metabolism*; D002478:Cells, Cultured; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D006706:Homeostasis / Q000187:drug effects*; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013450:Sulfones / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000633:toxicity*
chemical_list: D001572:Benzofurans; D001647:Bile Acids and Salts; D013450:Sulfones; C557331:TAK-875
keywords: bile acid inhibition; biliary excretion; drug induced liver injury; biomarkers