Randomised clinical trial: significant biochemical and colonic transit effects of the farnesoid X receptor agonist tropifexor in patients with primary bile acid diarrhoea.
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Camilleri M, Nord SL, Burton D, Oduyebo I, Zhang Y, Chen J, Im K, Bhad P, Badman MK, Sanders DS, Walters JRF
Randomised clinical trial: significant biochemical and colonic transit effects of the farnesoid X receptor agonist tropifexor in patients with primary bile acid diarrhoea.
Aliment Pharmacol Ther. 2020 Sep;52(5):808-820. doi: 10.1111/apt.15967. Epub 2020 Jul 23.
- PubMed ID
- 32702169 [ View in PubMed]
- Abstract
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 microg 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 microg/placebo [N = 10]; placebo/tropifexor 60 microg [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 7alpha-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 microg 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.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Tropifexor Bile acid receptor Protein Humans UnknownAgonistBinderDetails