title: Fasiglifam (TAK-875): Mechanistic Investigation and Retrospective Identification of Hazards for Drug Induced Liver Injury.
abstract: TAK-875, a GPR40 agonist, was withdrawn from Phase III clinical trials due to drug-induced liver injury (DILI). Mechanistic studies were conducted to identify potential DILI hazards (covalent binding burden (CVB), hepatic transporter inhibition, mitochondrial toxicity, and liver toxicity in rats) associated with TAK-875. Treatment of hepatocytes with radiolabeled TAK-875 resulted in a CVB of 2.0 mg/day, which is above the threshold of 1 mg/day considered to be a risk for DILI. Covalent binding to hepatocytes was due to formation of a reactive acyl glucuronide (AG) and, possibly, an acyl-CoA thioester intermediate. Formation of TAK-875AG in hepatocytes and/or in vivo was in the order of non-rodents > human (in vitro only) > rat. These data suggest that non-rodents, and presumably humans, form TAK-875AG more efficiently than rats, and that AG-mediated toxicities in rats may only occur at high doses. TAK-875 (1000 mg/kg/day) formed significant amounts of AG metabolite (≤32.7 μM) in rat liver that was associated with increases in ALT (×4), bilirubin (×9), and bile acids (×3.4), and microscopic findings of hepatocellular hypertrophy and single cell necrosis. TAK-875 and TAK-875AG had similar potencies (within 3-fold) for human multi-drug resistant associated protein 2/4 (MRP2/4) and bile salt export pump, but TAK-875AG was exceptionally potent against MRP3 (0.21 μM). Inhibition of MRPs may contribute to liver accumulation of TAK-875AG. TAK-875 also inhibited mitochondrial respiration in HepG2 cells, and mitochondrial Complex 1 and 2 activities in isolated rat mitochondria. In summary, formation of TAK-875AG, and possibly TAK-875CoA in hepatocytes, coupled with inhibition of hepatic transporters and mitochondrial respiration may be key contributors to TAK-875-mediated DILI.
authors.affiliation: Preclinical Development and Safety, Janssen Pharmaceuticals, Spring House, Pennsylvania 19477.
authors.forename: Monicah A
authors.initials: MA
authors.lastname: Otieno
authors.affiliation: Preclinical Development & Safety, Janssen Pharmaceutica NV, Beerse, Antwerpen BE 2340, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Snoeys
authors.affiliation: Preclinical Development and Safety, Janssen Pharmaceuticals, Spring House, Pennsylvania 19477.
authors.forename: Wing
authors.initials: W
authors.lastname: Lam
authors.affiliation: Preclinical Development and Safety, Janssen Pharmaceuticals, Spring House, Pennsylvania 19477.
authors.forename: Avi
authors.initials: A
authors.lastname: Ghosh
authors.affiliation: Cardiovascular & Metabolism, Janssen Pharmaceuticals, Spring House, Pennsylvania 19477.
authors.forename: Mark R
authors.initials: MR
authors.lastname: Player
authors.affiliation: Cardiovascular & Metabolism, Janssen Pharmaceuticals, Spring House, Pennsylvania 19477.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pocai
authors.affiliation: Preclinical Development and Safety, Janssen Pharmaceuticals, Spring House, Pennsylvania 19477.
authors.forename: Rhys
authors.initials: R
authors.lastname: Salter
authors.affiliation: Preclinical Development and Safety, Janssen Pharmaceuticals, Spring House, Pennsylvania 19477.
authors.forename: Damir
authors.initials: D
authors.lastname: Simic
authors.affiliation: Preclinical Development and Safety, Janssen Pharmaceuticals, Spring House, Pennsylvania 19477.
authors.forename: Hollie
authors.initials: H
authors.lastname: Skaggs
authors.affiliation: Preclinical Development and Safety, Janssen Pharmaceuticals, Spring House, Pennsylvania 19477.
authors.forename: Bhanu
authors.initials: B
authors.lastname: Singh
authors.affiliation: Preclinical Development and Safety, Janssen Pharmaceuticals, Spring House, Pennsylvania 19477.
authors.forename: Heng-Keang
authors.initials: HK
authors.lastname: Lim
mesh_terms: D000818:Animals; D001572:Benzofurans / Q000378:metabolism / Q000633:toxicity*; D056486:Chemical and Drug Induced Liver Injury / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008252:Macaca fascicularis; D008930:Mitochondria, Liver / Q000187:drug effects* / Q000502:physiology; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D027361:Organic Anion Transporters / Q000037:antagonists & inhibitors* / Q000235:genetics; D010101:Oxygen Consumption / Q000187:drug effects; D011485:Protein Binding; D051381:Rats; D013045:Species Specificity; D013450:Sulfones / Q000378:metabolism / Q000633:toxicity*
chemical_list: D001572:Benzofurans; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D027361:Organic Anion Transporters; D013450:Sulfones; C557331:TAK-875