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Randomised clinical trial: significant biochemical and colonic transit effects of the farnesoid X receptor agonist tropifexor in patients with primary bile acid diarrhoea
Author(s) -
Camilleri Michael,
Nord Sara Linker,
Burton Duane,
Oduyebo Ibironke,
Zhang Yiming,
Chen Jin,
Im Koeun,
Bhad Prafulla,
Badman Michael K.,
Sanders David S.,
Walters Julian R. F.
Publication year - 2020
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.15967
Subject(s) - fgf19 , farnesoid x receptor , medicine , tolerability , placebo , bile acid , gastroenterology , adverse effect , ursodeoxycholic acid , pharmacokinetics , agonist , receptor , fibroblast growth factor , biochemistry , chemistry , pathology , nuclear receptor , transcription factor , gene , alternative medicine
Summary Background In primary bile acid diarrhoea, feedback by farnesoid X receptor (FXR) and fibroblast growth hormone 19 (FGF19) on hepatic bile acid production is impaired. Aims To evaluate the safety, mechanisms and efficacy of negative feedback by FXR activation with tropifexor, a non‐bile acid FXR agonist, in patients with primary bile acid diarrhoea. Methods In this double‐blind, multicentre, randomised, cross‐over study, patients received tropifexor 60 µg or placebo once daily for 14 days in each of two treatment periods. Primary objectives included tropifexor safety and tolerability, and on stool frequency and form. Other assessments included pharmacokinetic and pharmacodynamic measures, biochemical markers and gastrointestinal transit. Results Twenty patients (tropifexor 60 µg/placebo [N = 10]; placebo/tropifexor 60 µg [N = 10]) were enrolled. Adverse event rates were lower with tropifexor vs placebo (52.9% vs 73.7%). No patient had pruritus during tropifexor intake. There were no significant differences in stool frequency, stool form or loperamide use between treatments. Tropifexor increased FGF19 and decreased 7α‐hydroxy‐4‐cholesten‐3‐one (C4) levels for up to 8 h. Plasma tropifexor concentrations peaked at 5 hours post‐dose on days 1 and 12. At day 12, tropifexor caused reduction in peak total bile acid concentration (33%, P = 0.032) and exposure (36%, P = 0.005). Moreover, tropifexor showed a significant increase in ascending colon half‐emptying time ( P = 0.036). Conclusions Tropifexor 60 µg once daily had acceptable safety and tolerability. Changes in FGF19 and C4 showed effective target engagement; however, higher doses may be required to observe stool frequency changes. Slowing of ascending colon emptying suggests therapeutic potential of tropifexor in patients with primary bile acid diarrhoea. ClinicalTrials.gov number: NCT02713243.