Effect of Hepatic Impairment on Eluxadoline Pharmacokinetics

Irritable bowel syndrome (IBS) is a chronic gastrointestinal disorder characterized by recurrent abdominal pain and altered bowel movements that is subtyped as predominantly diarrheal (IBS-D), constipating, or mixed/alternating between diarrhea and constipation.1 The global presence of IBS is approximately 11%, with one-third of all IBS cases being IBS-D.2,3 Patients with IBS-D commonly experience multiple symptoms, including bloating, abdominal pain, urgency, and diarrhea, ranging in levels of severity from mild and intermittent to severe and continuous.4 The burden of symptoms experienced by patients with IBS-D is associated with significant reductions in quality of life and increased use of healthcare resources.5,6 These burdens emphasize the need for pharmacological treatments to more effectively manage IBS-D symptoms. FDA-approved therapies for adults with IBS-D include eluxadoline, rifaximin, and alosetron (specifically for women with severe IBS-D).7 Eluxadoline (Viberzi; Furiex Pharmaceuticals, Inc, a subsidiary of Allergan plc, Parsippany, New Jersey) is a mixed μ-opioid receptor and κ-opioid receptor agonist and δ-opioid receptor antagonist that is locally active in the gastrointestinal tract.8 In 2 phase 3 clinical trials, eluxadoline 75mg and 100mg twice daily demonstrated efficacy in improving the abdominal pain and stool consistency associated with IBS-D, measured by a composite efficacy end point combining stool consistency and abdominal pain responses.9 Eluxadoline was well tolerated; clinical trials have shown that incidence rates of adverse events (AEs) and serious AEs were similar between eluxadoline-treated groups (at 75-mg and 100-mg doses) compared with those receiving placebo.10 The most common yet infrequent AE was constipation; discontinuation due to constipation was low. Treatment-emergent AEs tended to occur within the first few weeks after initiation of treatment. In nonclinical studies of cannulated rats low levels of eluxadoline were detectable in the hepatic portal vein after oral administration, although concentrations in the jugular vein were mostly below detectable levels.11 Additional evidence demonstrated that eluxadoline has poor oral bioavailability in humans (1.02%), primarily due to low gastrointestinal permeability (2.3%) but also resulting from hepatic first-pass extraction (55.8%).12 These results suggest that the liver plays an important role in the clearance of eluxadoline. The aim of this study, which was completed prior to the approval of eluxadoline, was therefore to determinewhether hepatic impairment has any clinically relevant effect on exposure to eluxadoline by assessment of the pharmacokinetic (PK), safety, and tolerability profile of a single oral dose of eluxadoline.