elobixibat and Irritable-Bowel-Syndrome

A number of new medications were recently demonstrated to be more effective than placebo in treating chronic constipation, including the intestinal chloride channel activator lubiprostone, the prokinetic selective 5-HT4 receptor agonist prucalopride and the guanylate cyclase-C agonist linaclotide. Recent publications have also revisited traditional laxatives like PEG. Moreover, a number of pharmacological treatments are in development and these include another guanylate cyclase-C agonist, plecanatide and an ileal bile acid transporter inhibitor, elobixibat.. This review focuses on the pharmacology, efficacy and safety profile of prucalopride, linaclotide, plecanatide and elobixibat.. The possible present or future clinical application of prucalopride, linaclotide, plecanatide and elobixibat in both chronic constipation and irritable bowel syndrome with constipation is reported, and some considerations on the possible role of PEG taking into account recent literature are advanced.

Topics: Benzofurans; Chronic Disease; Constipation; Dipeptides; Humans; Irritable Bowel Syndrome; Laxatives; Natriuretic Peptides; Peptides; Thiazepines

Bile acids are increasingly implicated in the pathogenesis of functional GI disorders. New mechanisms have recently been described in the irritable bowel syndrome, chronic diarrhea and chronic idiopathic constipation. Identification of bile acid signaling through farnesoid X receptor (FXR), transmembrane G-coupled receptor 5 (TGR5) and fibroblast growth factor 19 (FGF19) has led to the development of new, directly acting therapeutic agents. Despite these advances primary bile acid diarrhea remains under-recognized partly because of the lack of a widely available diagnostic test.. In this review we will summarize the effects of bile acids on bowel function throughout the gastrointestinal tract and their roles in the pathogenesis of functional diseases. We will review established diagnostic tests and therapies for functional heartburn, dyspepsia and bile acid diarrhea. There will be a particular emphasis on recent trial data for emerging therapies such as Elobixibat and Obeticholic acid and novel diagnostic tests for bile acid diarrhea such as 7α-Hydroxy-4-cholesten-3-one (C4) and FGF19. Finally we will discuss future directions for research in this rapidly evolving field, such as bacterial bile acid modification and identification of genetic anomalies associated with functional disorders.

Topics: Antidiuretic Agents; Bile Acids and Salts; Chenodeoxycholic Acid; Diarrhea; Dipeptides; Fibroblast Growth Factors; Gastrointestinal Diseases; Humans; Irritable Bowel Syndrome; Thiazepines

Elobixibat is an oral treatment candidate for chronic constipation with a novel mechanism of action via inhibition of the ileal bile acid transporter. We performed this randomized, double-blind, placebo-controlled, dose-finding phase IIb study in Japanese patients with chronic constipation to determine the optimal clinical dose of elobixibat.. Japanese patients with chronic constipation were randomized to receive elobixibat (5, 10, or 15 mg) or placebo once daily for 2 weeks. The primary efficacy endpoint was the change from baseline in frequency of spontaneous bowel movements at Week 1 of treatment. Secondary endpoints and adverse events were also examined.. Among 226 patients who provided informed consent, 163 patients were randomized and included in the full analysis set. In the 10- and 15-mg groups, frequency of spontaneous bowel movements (±standard deviation) were significantly higher than baseline (5.7 ± 4.2 and 5.6 ± 3.5 times per week, respectively, compared with 2.6 ± 2.9 times per week in the placebo group [P = 0.0005, P = 0.0001, respectively]). Subgroup analysis indicated that elobixibat was equally effective in patients with or without constipation-predominant irritable bowel syndrome. Common adverse events included mild abdominal pain and diarrhea in the elobixibat groups; no serious or severe adverse events occurred. Elobixibat was well tolerated at once-daily oral doses up to 15 mg for 2 weeks.. Our study results suggest that 10 mg of elobixibat is a clinically optimal dose for Japanese patients with chronic constipation.. JapicCTI-142608.

Topics: Administration, Oral; Adult; Aged; Carrier Proteins; Chronic Disease; Constipation; Defecation; Dipeptides; Dose-Response Relationship, Drug; Double-Blind Method; Female; Gastrointestinal Agents; Humans; Irritable Bowel Syndrome; Male; Membrane Glycoproteins; Middle Aged; Thiazepines; Young Adult