title: The ileal bile acid transporter inhibitor A4250 decreases serum bile acids by interrupting the enterohepatic circulation.
abstract: BACKGROUND
  Reabsorption of bile acids from the intestine by ileal bile acid transporter is pivotal for the enterohepatic circulation of BAs and sterol homoeostasis.
  
  
  OBJECTIVE
  To assess tolerability and study, bile acid metabolism in a phase 1 trial with the selective ileal bile acid transporter inhibitor A4250.
  
  
  METHODS
  A randomised double-blind, single-ascending dose (SAD) and multiple-ascending-dose study consisting of five cohorts comprising 40 individuals with a single administration of A4250 (0.1, 0.3, 1, 3, or 10 mg) or placebo and three cohorts comprising 24 individuals with a 1-week administration of A4250 (1 or 3 mg once daily or 1.5 mg twice daily) or placebo. For the multiple-ascending-dose study, bile acids were measured by HPLC-MS in plasma and faeces, and fibroblast growth factor 19 (FGF19) and 7α-hydroxy-4-cholesten-3-one (C4) were measured in plasma.
  
  
  RESULTS
  No serious adverse events occurred and all participants finished the trial per protocol. At the end of the multiple-ascending-dose study, plasma total bile acids and FGF19 decreased by 47% and 76%, respectively, at 3 mg/day (P < 0.01), and by 15% and 16%, respectively, at 1.5 mg twice daily (P < 0.05). Plasma C4 and faecal bile acids increased at all dose regimens, by 555%, 664%, 292% and 338%, 421%, 420%, respectively (P < 0.01-0.05). The primary bile acids cholic and chenodeoxycholic acids constituted the majority of faecal bile acids in the A4250-treated groups.
  
  
  CONCLUSIONS
  A4250 is well tolerated. By blocking ileal bile acid transporter in the terminal ileum, it highly efficiently interrupts the enterohepatic circulation of BAs, and should be of benefit to patients with cholestatic liver diseases. Clinical Trial registration EudraCT 2013-001175-21.
authors.affiliation: Albireo, Gothenburg, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Graffner
authors.affiliation: Albireo, Gothenburg, Sweden.|Department of Neurobiology, Care Sciences and Society, Center for Alzheimer Research, Division of Translational Alzheimer Neurobiology, Karolinska Institutet, Novum, Stockholm, Sweden.
authors.forename: P-G
authors.initials: PG
authors.lastname: Gillberg
authors.affiliation: Albireo, Gothenburg, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Rikner
authors.affiliation: Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
authors.forename: H-U
authors.initials: HU
authors.lastname: Marschall
mesh_terms: D000328:Adult; D001647:Bile Acids and Salts / Q000378:metabolism*; D002352:Carrier Proteins / Q000037:antagonists & inhibitors*; D002635:Chenodeoxycholic Acid / Q000378:metabolism; D002783:Cholestenones / Q000097:blood; D004311:Double-Blind Method; D004764:Enterohepatic Circulation / Q000187:drug effects*; D005243:Feces / Q000737:chemistry; D005260:Female; D005346:Fibroblast Growth Factors / Q000097:blood; D006801:Humans; D007082:Ileum / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*
chemical_list: D001647:Bile Acids and Salts; D002352:Carrier Proteins; D002783:Cholestenones; C117476:FGF19 protein, human; D008562:Membrane Glycoproteins; C037643:bile acid binding proteins; D002635:Chenodeoxycholic Acid; C002656:7 alpha-hydroxy-4-cholesten-3-one; D005346:Fibroblast Growth Factors