Eluxadoline in irritable bowel syndrome with diarrhea: rationale, evidence and place in therapy

Abstract

Irritable bowel syndrome (IBS) is the most common gastrointestinal (GI) disorder worldwide, however treatment options for diarrhea-predominant IBS (IBS-D) remain limited. Eluxadoline, a µ- and κ-opioid receptor agonist and δ-opioid receptor antagonist, was recently approved for the treatment of IBS-D. A novel compound first described in 2008, eluxadoline was shown to normalize GI transit, with a subsequent phase I demonstrating its safety and tolerability in healthy adults. In 2016, two randomized, double-blind, placebo-controlled phase III trials studying eluxadoline use at 75 mg and 100 mg twice daily over 26 weeks demonstrated a significant improvement in stool consistency and many global symptoms of IBS. However, the data did not demonstrate a significant advantage over placebo using the United States Food and Drug Administration (US FDA) and European Medicines Agency (EMA) endpoints for abdominal pain. Safety and tolerability data, pooled from both phase II and III studies, suggest that eluxadoline is generally well tolerated with the most common adverse events (AEs) occurring in approximately 3-8% of patients and included nausea, constipation, and abdominal pain. The most common serious adverse event (SAE) is pancreatitis, which had a 0.4% incidence. Recent US FDA reports reporting severe pancreatitis and sphincter of Oddi dysfunction after short-term use of eluxadoline in patients without a gallbladder has added a history of cholecystectomy as an important contraindication. Eluxadoline is also contraindicated in patients with a history of biliary duct obstruction, sphincter of Oddi dysfunction, active alcohol abuse, history of pancreatitis or known pancreatic duct obstruction, severe hepatic impairment, severe or chronic constipation, or known mechanical gastrointestinal obstruction. As a new drug to enter the IBS-D market, the place of eluxadoline in the hierarchy of IBS treatments is still to be determined. In this article, we review the development and clinical trial data behind the approval of eluxadoline with a focus on safety data and its use in clinical practice.

Sex-Gender Differences in Irritable Bowel Syndrome

“…Eluxadoline 100 mg peroral bid μ-and κ-opioid receptor agonist and δ-opioid receptor antagonist Efficacious in both men and women. 117,118 Contraindicated in patients with history of cholecystectomy.…”

“…97 Linaclotide, a guanylate cyclase C receptor agonist, has been shown to be effective in both women and men IBS patients with constipation and chronic idiopathic constipation. 117,125 Eluxadoline, a μ-and κ-opioid receptor agonist and δ-opioid receptor antagonist which has been approved as a therapeutic agent for IBS-D, 118 has been associated with reduced abdominal pain and improved stool consistency in both women and men receiving 100 mg twice daily with sustained efficacy for more than 6 months in large, randomized, placebo-controlled trials (Table). 126 Patients with IBS have altered intestinal microbiota compared to healthy individuals.…”

Irritable Bowel Syndrome: News from an Old Disorder

“…Eluxadoline is a new oral agent with peripherally acting mixed μ-opioid receptor agonist-δ-opioid receptor antagonist and κ-opioid receptor agonist that slows GI motility and decreases visceral hypersensitivity [81]. Reports of severe pancreatitis and sphincter of Oddi dysfunction, particularly in patients without a gallbladder or those who abuse alcohol, led to the contraindication of eluxadoline in these groups of patients [82]. 5-HT 3 receptor antagonists are effective in patients with IBS-D, both slowing colonic transit through the inhibition of peristaltic reflex [83] and modulating visceral nociception [30].…”

Inhibition of CFTR‐mediated intestinal chloride secretion as potential therapy for bile acid diarrhea

“…For IBS-D, in which BAD is likely involved in pathogenesis in more than one-third of patients (1,2), FDA-approved therapies include the 5-hydroxytryptamine type 3 antagonist alosetron, the mixed m opioid receptor agonist eluxadoline, and the broad-spectrum gut-specific antibiotic rifaximin. Other commonly used therapies for IBS-D include loperamide, bile acid sequestrants, antispasmodics, and tricyclic antidepressants (33)(34)(35). Some of these therapies are associated with significant side effects such as ischemic colitis with alosetron and pancreatitis with eluxadoline (35).…”