An Open‐Label Study to Evaluate the Effect of Eluxadoline on the Single‐Dose Pharmacokinetics of Midazolam in Healthy Participants

Eluxadoline is a mixed μ‐opioid, κ‐opioid receptor agonist, and δ‐opioid receptor antagonist, approved in the United States for adults with diarrhea‐predominant irritable bowel syndrome. This phase 1, single‐center, open‐label, single‐sequence study was conducted on 30 healthy participants to establish whether steady‐state eluxadoline increases systemic exposure of the cytochrome P450 (CYP) 3A4 substrate midazolam. Participants received oral midazolam 4 mg on day 1 with a 7‐day washout period. On days 8‐16, oral eluxadoline 100 mg was administered twice daily. On day 15, midazolam 4 mg was coadministered with the eluxadoline 100‐mg morning dose. Primary outcome measures were pharmacokinetic parameters of midazolam and 1‐hydroxy‐midazolam. The midazolam and 1‐hydroxy‐midazolam geometric mean ratios and 90%CIs for maximum plasma drug concentration were 99.0% (91.6‐107.0) and 113.8% (104.9‐123.5), respectively, and area under the plasma concentration–time curves were 90.5% (83.9‐97.6) and 105.1% (99.8‐110.7), respectively, demonstrating the 2 treatments were bioequivalent, and there was no clinically significant drug interaction. All treatment‐emergent adverse events were treatment related, mild in intensity, with no serious adverse events. These results suggest that eluxadoline has no clinically significant effect on CYP3A4 activity and is, therefore, unlikely to affect the pharmacokinetics of other CYP3A4 substrates.