Extent of Fentanyl Accumulation Following Multiple Doses of Fentanyl Buccal Tablet 400 microg in Healthy Japanese Volunteers.

ABSTRACT

OBJECTIVE: This study was conducted to characterize the pharmacokinetics, including extent of accumulation, and safety and tolerability of fentanyl following multiple doses of fentanyl buccal tablet (FBT) in healthy Japanese volunteers. METHODS: Healthy Japanese adults received 10 successive doses of open-label FBT 400 microg at 6-hour intervals. Naltrexone was given to minimize the opioid effects of fentanyl. FBT was placed above a molar tooth between the gum and cheek. Peak serum fentanyl concentration (C(max)), time to C(max) (t(max)), and area under the serum fentanyl concentration-time curve from 0 to 6 hours (AUC(0-6)) were summarized using descriptive statistics. Accumulation ratio was calculated as C(max) for dose 10/C(max) for dose 1, and was calculated similarly for AUC(0-6). RESULTS: Fourteen volunteers (mean age 33 years) were enrolled, and 13 completed the study. After doses 1 and 10, respectively, mean (SD) C(max) was 1.70 (0.49) ng/mL and 1.97 (0.42) ng/mL, AUC(0-6) was 4.46 (1.14) ng.h/mL and 6.81 (0.90) ng.h/mL, and median (range) t(max) was 50 (30-110) minutes and 30 (15-120) minutes. Following 10 successive doses, systemic exposure (AUC(0-6)) was 55% higher than after dose 1, and C(max) was 23% higher. Steady state was achieved within 3 days of dosing at 6-hour intervals, i.e., prior to dose 10. The most frequent adverse events (AEs) were somnolence (N = 9), decreased oxygen saturation (N = 4), headache (N = 3), application-site pain (N = 8), application-site erythema (N = 6), and application-site reaction (N = 5). All AEs were mild or moderate. CONCLUSIONS: Following administration of FBT at 6-hour intervals to healthy Japanese volunteers, at steady state, fentanyl exposure was higher by 55% (AUC(0-6)) and 23% (C(max)) than after a single dose of FBT. Adverse events were mild or moderate.