Pharmacokinetics of Fentanyl Sublingual Spray in Opioid-Naïve Participants: Results of a Phase 1, Multiple Ascending Dose Study

Abstract

Background and Objectives: Fentanyl sublingual spray may be a viable alternative to intravenous (IV) opioids for the treatment of acute pain. As patients with acute pain may include those who have limited prior exposure to opioids, this phase 1, open-label, randomized, multiple ascending-dose study was conducted to assess the pharmacokinetics, pharmacodynamics, safety, and tolerability of multiple doses of fentanyl sublingual spray in opioid-naïve participants. This article primarily reports the pharmacokinetics results. Methods: Study drugs were administered in four dosing cohorts: every 0.5, 1, 2, or 4 h for a maximum of three doses per cohort. Eight fasted individuals per cohort were randomized to either fentanyl sublingual spray (100, 200, or 400 µg) or fentanyl citrate IV 50 µg (6:2 ratio). Blood samples were collected pre-dose through 24 h post first dose. Results: A total of 98 healthy adults were enrolled and 96 completed the study. Mean plasma fentanyl concentrations increased with increasing doses of fentanyl sublingual spray administered every 0.5–4 h. With multiple doses, systemic exposure increased relative to the first dose; shorter dosing intervals resulted in higher concentrations. Analysis of dose proportionality suggested that systemic exposure increased in a linear but slightly greater than dose-proportional manner. Accumulation between the first and last doses of fentanyl sublingual spray was more pronounced with shorter dosing intervals. Conclusion: Dose-dependent fentanyl pharmacokinetics following multiple doses of fentanyl sublingual spray were well characterized in an opioid-naïve population. ClinicalTrials.gov identifier: NCT02641340.