Relative Bioavailability of Fentanyl Following Various Dosing Regimens of Fentanyl Buccal Tablet in Healthy Japanese Volunteers.

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.

Dose Proportionality of Fentanyl Buccal Tablet in Healthy Japanese Volunteers.

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.

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

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.

Relative bioavailability of the fentanyl effervescent buccal tablet (FEBT) 1,080 pg versus oral transmucosal fentanyl citrate 1,600 pg and dose proportionality of FEBT 270 to 1,300 microg: 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 bioavailability of FEBT 1,080 microg with that of oral transmucosal fentanyl citrate (OTFC) 1,600 microg, and the secondary objective was to assess the dose proportionality of FEBT 270 to 1,300 microg in healthy adult volunteers. METHODS: This single-dose, randomized, open-label, 3-period study was conducted by MDS Pharma Services, Lincoln, Nebraska. Non-opioid-tolerant healthy adult volunteers were included. In periods 1 and 2 (relative-bioavailability analysis), subjects were randomly assigned to 1 of 2 administration sequences: single-dose FEBT 1,080 microg followed by single-dose OTFC 1,600 microg, or vice versa; in period 3 (dose-proportionality analysis), they were randomly assigned to receive a single dose of FEBT 270, 810, or 1,300 microg. 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 microg, 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 [SD] 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 1,080 microg and OTFC 1,600 microg (mean [SD], 18.0 [5.4] vs 18.0 [7.1] ng x h/mL). However, the mean (SD) C(max) with FEBT 1,080 microg was 2.7 (0.9) ng/mL compared with 2.2 (0.7) ng/mL with OTFC 1,600 microg (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 microg]) was significantly greater with FEBT compared with OTFC (1.5 [0.5] vs 0.8 [0.4] ng x 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 1,300 microg. Increases in C(max) were less than dose proportional at FEBT doses >810 microg. Definitive attribution of adverse events (AEs) to FEBT or OTFC was generally not possible because these medications were coadministered with naltrexone. With naltrexone alone, there were reports of headache (3 [7%] subjects), nausea (1 [2%]), upset stomach (1 [2%]), and low systolic blood pressure (1 [2%]) after naltrexone administration, but before FEBT or OTFC administration. The AEs were typical of opioids (ie, headache, nausea, lightheadedness), and most (89.6%) were mild. One case each of mild oral irritation and redness were reported after the administration of FEBT Both occurrences resolved within 4.5 hours after study drug administration. No irritation or redness was reported after the administration of OTFC. CONCLUSIONS: In this pharmacokinetic study in healthy volunteers, total systemic exposure increased in a dose-proportional manner up to FEBT 1,300 microg, whereas doses above 810 microg showed a less-than-dose-proportional increase in C(max). The results suggest that fentanyl enters the systemic circulation to a significantly greater extent (C(max) and AUC(0-Tmax')) and significantly more rapidly (T(max)) with FEBT compared with OTFC.

Pharmacokinetics and dose proportionality of fentanyl effervescent buccal tablets in healthy volunteers.

BACKGROUND AND OBJECTIVES: Fentanyl effervescent buccal tablets (FEBT) are designed to enhance the rate and efficiency of fentanyl absorption through the buccal mucosa. This study was undertaken to characterise the pharmacokinetics and assess the dose proportionality of FEBT in healthy volunteers within the potential therapeutic dose range. METHODS: Twenty-five healthy adults (mean age 33 years) completed a single-dose, randomised, open-label, four-dose, four-period, crossover study of FEBT. They were administered FEBT 200, 500, 810 or 1080microg. The subjects in this study were not opioid tolerant; therefore, naltrexone was administered to block any opioid receptor-mediated effects of fentanyl. Venous blood samples for measurement of serum fentanyl concentrations were obtained over 36 hours following dosing. Adverse events were recorded throughout the study. RESULTS: The pharmacokinetics of FEBT were characterised by an absorption phase with a median time to reach maximum serum concentration (tmax) of 0.75-0.99 hours that was consistent irrespective of dose. Mean serum fentanyl concentrations exhibited a biexponential decline from peak after FEBT 200 and 500microg doses and a triexponential decline after FEBT 810 and 1080microg doses. The maximum serum concentration (Cmax) of fentanyl was proportional up to and including the 810microg dose. The increase in Cmax was 20% less than proportional at the 1080microg dose. Systemic exposure to fentanyl, as measured by the area under the serum concentration-time curve from time zero to infinity (AUCinfinity), increased proportionally with increasing doses of FEBT (200-1080microg). No serious adverse events were reported during the study. CONCLUSION: The pharmacokinetics of FEBT were characterised by a high early fentanyl concentration as a result of absorption across the buccal mucosa of the oral cavity, which results in bypassing first-pass metabolism. This high early tmax contributed to enhanced early systemic fentanyl exposure. Maximum concentration and AUCinfinity of FEBT increased in a dose-proportional manner from 200 to 810microg. This study provides preliminary pharmacokinetic data for FEBT across the potential therapeutic dose range.