Dose Proportionality of Fentanyl Buccal Tablet in Healthy Japanese Volunteers

Abstract

Objective. This study was conducted to assess the dose proportionality, safety, and tolerability of fentanyl buccal tablet (FBT) in Japanese volunteers.

Methods. Healthy, opioid-naive Japanese adults received single-dose FBT 100, 200, 400, and 800 µg in a randomized, open-label, crossover fashion. Naltrexone was given to minimize the opioid effects of fentanyl. Peak serum fentanyl concentration (C_max), time to C_max (t_max), area under the serum fentanyl concentration-time curve (AUC) from time 0 to infinity (AUC_0–∞), and AUC from 0 to the last quantifiable concentration (AUC_0–last) were summarized using descriptive statistics. Dose proportionality was claimed if the ln-ln plots of C_max, AUC_0–∞, and AUC_0–last vs. dose were linear and the 90% confidence intervals (CI) of the slopes were within 0.8927 and 1.1073. The safety population comprised volunteers who received ≥1 FBT.

Results. Twenty-five volunteers were enrolled, 23 were included in the safety population (mean age 35.3 years), and 19 completed the study. The assessment of dose proportionality did not meet the statistical criteria (slope [90% CI]: 0.9118 [0.8601, 0.9635] for C_max, 1.0756 [1.0377, 1.1136] for AUC_0–∞, and 1.0992 [1.0677, 1.1307] for AUC_0–last). However, the increase in systemic exposure with dose appeared linear, and a post hoc analysis of partial AUCs from time 0 to 8, 12, 18, and 24 hours supported dose proportionality. Median t_max of 90 minutes (range 30–180 minutes) was independent of dose. Adverse events (AEs) were mild or moderate. The most frequent AEs were nausea (N = 9), dizziness (N = 8), headache (N = 6), somnolence (N = 6), dyspepsia (N = 5), and vomiting (N = 3). No application-site or serious AEs were reported.

Conclusions. Systemic exposure to FBT was approximately dose proportional across the range 100 µg to 800 µg in healthy Japanese adults. Adverse events were mild or moderate.