Relative bioavailability of the fentanyl effervescent buccal tablet (FEBT) 1080 μg versus oral transmucosal fentanyl citrate 1600 μg and dose proportionality of FEBT 270 to 1300 μg:: A single-dose, randomized, open-label, three-period study in healthy adult volunteers

Background: The fentanyl effervescent buccal tablet (FEBT) was designed to enhance the rate and extent of absorption of fentanyl through the buccal mucosa. FEBT is being investigated for the management of breakthrough pain. Objectives: The primary objective of this study was to compare the relative bloavailability of FEBT 1080 mu g with that of oral transmucosal fentanyl citrate (OTFC (R)) 1600 mu g, and the secondary objective was to assess the dose proportionality of FEBT 270 to 1300 mu g in healthy adult volunteers. Methods: This single-dose, randomized, open-label, 3 period study was conducted by MDS Pharma Services, Lincoln, Nebraska. Non-oploid-tolerant healthy adult volunteers were included. In periods I and 2 (relative-bioavailability analysis), subjects were randomly assigned to 1 of 2 administration sequences: single-dose FEBT 1080 mu g followed by single-dose OTFC 1600 jag, or vice versa; in period 3 (doseproportionality analysis), they were randomly assigned to receive a single dose of FEBT 270, 810, or 1300 mu g. Subjects were instructed to place FEBT between the gum and cheek above an upper molar tooth and allow it to disintegrate for 10 minutes. Subjects were instructed to place the OTFC lozenge between the cheek and lower gum and move the unit from side to side using the handle and allow the unit to dissolve for 15 minutes. All subjects received naltrexone 50 mg PO at 15 and 3 hours before and 12 hours after fentanyl administration, except those receiving FEBT 270 pg, who were not given naltrexone at 12 hours. For the measurement of serum concentrations of fentanyl, venous blood samples were collected before and up to 36 hours after study drug administration. For tolerability analysis, continuous pulse oximetry, 12-lead electrocardiography, clinical laboratory analysis, and physical examination, including vital-sign measurements, were performed; the oral mucosa was inspected; and spontaneous reporting was employed. Results: A total of 42 subjects were enrolled (25 women, 17 men; mean [SDI age, 27 [11] years; mean [SD] weight, 68.4 [8.7] kg); 39 completed the study. Total systemic exposure (as measured using AUC(0-infinity)) was statistically similar between FEBT 1080 pg and OTFC 1600 pg (mean [SD], 18.0 [5.4] vs 18.0 [7.1] ng (.) h/mL). However, the mean (SD) C-max with FEBT 1080 pg was 2.7 (0.9) ng/mL compared with 2.2 (0.7) ng/mL with OTFC 1,600 pg (P = NS), and the T-max of 1.0 hour with FEBT was significantly less compared with OTFC (2.0 hours; P < 0.001). Similarly, mean (SD) early systemic exposure (AUC(0-Tmax'); ie, AUC from time 0 to 1 hour [the median T-max of the reference dose of FEBT [810 mu g]) was significantly greater with FEBT compared with OTFC (1.5 [0.5] vs 0.8 [0.4] ng (.) h/mL; P < 0.001). Exploratory analyses suggested dose proportionality as assessed using AUC(0-infinity) and AUC(0-Tmax') over the range of FEBT 270 to 1300 mu g.