Elobixibat for the treatment of constipation

Abstract

Chronic idiopathic constipation (CC) is highly prevalent worldwide. A subset of patients with CC have reduced fecal (and by inference, intra-colonic) bile acids (BA). Elobixibat, a locally-acting ileal bile acid transporter (IBAT) inhibitor, leads to increased BA delivery to the colon and represents a new class of treatment for CC. BAs accelerate colonic transit and increase colonic secretion. Therefore, IBAT inhibitors have potential to treat patients with CC. Areas covered: Rationale for IBAT inhibitor in therapeutics, and preclinical and clinical pharmacology of elobixibat: In vitro, elobixibat is a highly potent, selective IBAT inhibitor. In humans, elobixibat accelerated colonic transit. In phase 2A, 2B and 3 studies in CC, elobixibat was efficacious, well tolerated and safe. An open-label, phase 3 trial (52 weeks) confirmed the safety of elobixibat. Elobixibat reduces LDL cholesterol, increases serum GLP-1, and has potential in metabolic syndrome. Expert commentary: Uniquely among current treatments of CC, elobixibat stimulates both motor and secretory functions in the colon. These dual effects suggest that, when approved, elobixibat may be a first-line choice for constipation associated with colonic BA deficiency and a second-line treatment for all patients with CC and constipation-predominant irritable bowel syndrome. Further studies are required to confirm efficacy for relief of CC. Once approved, elobixibat will likely become a second-line choice for treatment of CC.

Keywords: Bile acid; enterohepatic circulation; ileal bile acid transporter (IBAT); irritable bowel syndrome; pharmacodynamics; pharmacokinetics.

Figure 1.. Chemical structures and colonic functions of individual bile acids. Modified with permission from reference 35.

BA, bile acids; CDCA, chenodeoxycholic acid; CA, cholic acid; DCA, deoxycholic acid; LCA, lithocholic acid; UDCA, ursodeoxycholic acid

Figure 2.

Enterohepatic circulation. The left panel shows the enterohepatic circulation in patients without bile acid malabsorption. The right panel demonstrates enterohepatic circulation in patients with bile acid malabsorption. Reproduced from reference [39] (no permission needed; it is a free PMC article). IBAT, ileal bile acid transporter; IBS, irritable bowel syndrome;

Figure 3.

Two dimensional molecular structure of elobixibat