RESUMO
BACKGROUND: Fentanyl buccal tablet (FBT; FENTORA(R), Cephalon, Inc., Frazer, PA, USA) is indicated in the US for breakthrough pain in patients with cancer who are already receiving and are tolerant to around-the-clock opioid therapy for underlying persistent cancer pain. For each individual patient, FBT should be titrated to the effective dose. OBJECTIVE: The primary objective was to characterize the pharmacokinetic parameters of FBT 400 microg administered as a single 400 microg tablet (regimen A) or as two 200 microg tablets given simultaneously (regimen B) and determine whether these are bioequivalent in healthy Japanese volunteers. Regimen C (two 200 microg tablets 30 minutes apart) was also compared as a secondary objective. METHODS: Healthy Japanese adults received regimens A, B, and C in a crossover fashion. Naltrexone was given to minimize the opioid effects of fentanyl. Serum fentanyl concentrations were determined in venous blood collected through 36 hours post dose. Regimens were declared bioequivalent with respect to bioavailability (as reflected by AUC(0-infinity), AUC(0-last), and C(max)) if the 90% confidence interval (CI) of the regimens' ratio fell within 0.80-1.25 (80%-125%). RESULTS: Twenty-nine volunteers (13 men, 16 women) were enrolled; 24 completed the study. Regimens A and B had bioequivalent systemic exposure parameters (B/A [90% CI]: AUC(0-infinity)108.4 [103.4, 113.7], AUC(0-last) 106.1 [100.7, 111.7], and C(max) 92.3 [83.2, 102.4]). Regimen C was bioequivalent to both A and B for AUCs, but only to B for C(max). Median time to C(max) was 45 minutes for regimen A and 60 minutes for regimens B and C. The most frequent AEs were dizziness, application-site erythema, headache, somnolence, nausea, and vomiting. All AEs were mild or moderate. CONCLUSIONS: Bioavailability of fentanyl after FBT 400 microg administered as a single tablet was bioequivalent to that after 2 simultaneously administered 200 microg tablets in healthy Japanese volunteers. AEs were mild or moderate.
RESUMO
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 microg 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-infinity)), 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-infinity), 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-infinity), 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 microg to 800 microg in healthy Japanese adults. Adverse events were mild or moderate.
RESUMO
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.