Pharmacokinetic properties of fentanyl effervescent buccal tablets: A phase I, open-label, crossover study of single-dose 100, 200, 400, and 800 μg in healthy adult volunteers *

Background: The fentanyl effervescent buccal tablet (FEBT) is designed to enhance the rate and extent of the absorption of fentanyl, an opioid, through the buccal mucosa.Objectives: The purposes of this study were to assess the dose proportionality of FEBT in healthy volunteers over the potential therapeutic dose range (100–800 μg) and characterize the pharmacokinetic (PK) profile of 4 doses (100, 200, 400, and 800 μg) of FEBT.Methods: This Phase I, randomized, open-label, 4-period crossover study was conducted at Radiant Research, Honolulu, Hawaii. Healthy adult volunteers with intolerance to opioids were randomly assigned to receive 1 of 4 single-dose sequences of FEBT: 100, 200, 400, and 800 μg (selected to encompass the anticipated therapeutic dose range), with each successive administration separated by a washout period of ≥7 days. Naltrexone hydrochloride (50-mg tablet) was administered-15 and 3 hours before and 9 hours after FEBT administration to block opioid receptor-mediated effects of fentanyl. Plasma fentanyl concentrations were measured from venous samples obtained over 72 hours after FEBT administration. Early fentanyl exposure was assessed using AUC from time 0 to 0.75 hour (the median Tmax of the reference dose [100 μg]) (AUC0-Tmax′). Adverse events (AEs) were monitored and recorded throughout the study by medically qualified personnel.Results: Thirty-two subjects (26 men, 6 women; mean [SD] age, 29.3 [7.2] years [range, 19–44 years]; mean [SD] weight, 74.7 [10.7] kg) were enrolled. Median T was between 35 and 45 minutes after FEBT administration. AUC0−∞ and Cmax increased approximately linearly with increasing doses of FEBT. Mean plasma fentanyl concentrations decreased from Cmax in a biexponential manner at the 100- and 200-μg doses and decreased in a triexponential manner at the 800-μg dose. Despite the triexponential decrease in the mean profile observed with the 400-μg dose, a biexponential decrease was observed in approximately half of the individual profiles. AUC0−Tmax′ ranged from 0.09 ng · h/mL with the 100-μg dose to 0.52 ng · h/mL with the 800-μg dose. The most commonly reported AEs in the 100-, 200-, 400-, and 800-μg dose groups were as follows: application-site erythema, 3, 3, 4, and 3 subjects, respectively; nausea, 3, 2, 5, and 4 subjects; somnolence, 3, 2, 3, and 2 subjects; and headache, 3, 2, 1, and 4 subjects. None of the AEs were serious.Conclusions: In this study of the dose proportionality of FEBT in healthy volunteers, the PK profile of FEBT was characterized by a high early systemic exposure of fentanyl (0.09–0.52 ng · h/mL). Dose-dependent parameters (Cmax and AUC) increased in an approximately dose-proportional manner from 100 to 800 μg FEBT.