Premium
The ileal bile acid transporter inhibitor A4250 decreases serum bile acids by interrupting the enterohepatic circulation
Author(s) -
Graffner H.,
Gillberg P.G.,
Rikner L.,
Marschall H.U.
Publication year - 2016
Publication title -
alimentary pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.308
H-Index - 177
eISSN - 1365-2036
pISSN - 0269-2813
DOI - 10.1111/apt.13457
Subject(s) - enterohepatic circulation , bile acid , fgf19 , chenodeoxycholic acid , medicine , placebo , endocrinology , tolerability , gastroenterology , ileum , taurocholic acid , adverse effect , fibroblast growth factor , receptor , alternative medicine , pathology
Summary Background Reabsorption of bile acids from the intestine by ileal bile acid transporter is pivotal for the enterohepatic circulation of BA s and sterol homoeostasis. Aim 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 ( FGF 19) 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 FGF 19 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 BA s, and should be of benefit to patients with cholestatic liver diseases. Clinical Trial registration EudraCT 2013‐001175‐21