John G. Jiang

Absolute and Relative Bioavailability of Fentanyl Buccal Tablet and Oral Transmucosal Fentanyl Citrate

This study assessed the absolute and relative bioavailabilities and transmucosal and gastrointestinal absorbency of fentanyl buccal tablet (FBT) and oral transmucosal fentanyl citrate (OTFC). In a randomized crossover design, 26 healthy subjects received FBT 400 μg (transmucosal), FBT 800 μg (oral), OTFC 800 μg (transmucosal), and fentanyl 400 μg (intravenous). The transmucosal FBT had the highest absolute bioavailability (0.65) compared with the oral FBT (0.31) or transmucosal OTFC (0.47). More fentanyl was absorbed transmucosally from FBT than OTFC (48% vs 22%). Median tmax values were shorter following the transmucosal FBT (47 minutes) than the oral FBT (90 minutes) or the transmucosal OTFC (91 minutes). Transmucosal administration of FBT compared with dose‐normalized OTFC resulted in higher total systemic fentanyl exposure, higher early systemic exposure, and higher Cmax. The rate and extent of fentanyl absorption were greater following administration of FBT compared to OTFC. An approximately 30% smaller dose of FBT achieved systemic exposures comparable to OTFC.

Single‐Dose and Steady‐State Pharmacokinetics of Fentanyl Buccal Tablet in Healthy Volunteers

This study evaluated the single‐dose and steady‐state pharmacokinetics of fentanyl buccal tablet 400 μg in healthy adult volunteers. After receiving naltrexone 50 mg to block opioid receptor–mediated effects of fentanyl, subjects received fentanyl buccal tablet 400 μg on day 1, then every 6 hours from day 4 to day 9 (21 doses). Naltrexone 50 mg was administered every 12 hours throughout the study. Plasma fentanyl concentrations were determined for 72 hours after administration of fentanyl buccal tablet 400 μg on day 1 and the last dose of fentanyl buccal tablet 400 μg on day 9. Following single‐ and multiple‐dose administration of fentanyl buccal tablet, the median time to maximum concentration (tmax) was 52.2 and 49.8 minutes, respectively. Peak plasma concentration of fentanyl (Cmax) was 0.88 ng/mL for the single‐dose regimen and 1.77 ng/mL for the multiple‐dose regimen. Steady state was reached within 5 days, consistent with the observed median half‐life of approximately 22 hours following multiple doses. Observed accumulation of fentanyl after multiple doses of fentanyl buccal tablet was slightly greater than would be expected based on the single‐dose data. This was attributed to the redistribution of fentanyl from a deep tissue compartment into the plasma. This study indicates that fentanyl buccal tablet has predictable pharmacokinetics following multiple‐dose administration.

Comparison of Equivalent Doses of Fentanyl Buccal Tablets and Arteriovenous Differences in Fentanyl Pharmacokinetics

BackgroundThe fentanyl buccal tablet (FBT) is designed to enhance the rate and extent of fentanyl absorption through the buccal mucosa.AimTo evaluate the bioequivalence of μg-equivalent doses of FBT administered as single and multiple tablets and assess differences in the arterial and venous pharmacokinetics of FBT in healthy volunteers.MethodsTwenty-seven healthy adults, aged 19–5 years, participated in the randomised, open-label, three-period, crossover study. In the first two periods, FBT was administered as four 100μg tablets simultaneously or one FBT 400μg to assess bioequivalence. Venous blood samples were obtained over a 72-hour period to measure plasma fentanyl concentrations. In the third period, arterial and venous blood samples were obtained simultaneously from before administration of one FBT 400μg through 4 hours after administration to evaluate the impact of arterial versus venous sampling on the pharmacokinetic profile. As subjects were not opioid tolerant, naltrexone was administered to block opioid receptor-mediated effects of fentanyl. Adverse events were recorded throughout.ResultsMaximum plasma concentration (Cmax) and area under the plasma concentration-time curve from time zero to infinity (AUC∞) on average were approximately 12% and 13% higher, respectively, for FBT administered as four 100μg tablets simultaneously compared with one FBT 400μg. Maximum plasma concentrations in the arterial circulation were approximately 60% higher and occurred 15 minutes earlier than those measured from the venous circulation. No serious adverse events were reported during the study.ConclusionDespite small differences in Cmax and AUC∞ (on average 12% and 13%, respectively), FBT administered as four 100μg tablets simultaneously compared with one 400μg tablet did not meet the criteria for bioequivalence. An increased surface area exposure with four tablets compared with one tablet may account for the slightly higher maximum concentrations observed with four 100μg tablets. A substantially higher Cmax was reached earlier in the arterial than in the venous circulation.

Absorption of fentanyl from fentanyl buccal tablet in cancer patients with or without oral mucositis : A pilot study

AbstractBackground and objectives: Patients with cancer, particularly those undergoing chemotherapy or radiotherapy, may develop oral mucositis. This is the first study to investigate the absorption profile of fentanyl buccal tablet (FBT) — an effervescent formulation of fentanyl indicated for the management of breakthrough pain in opioid-tolerant cancer patients — in patients with or without oral mucositis. Methods: In this open-label study, patients with or without oral mucositis self-administered a single 200μg dose of FBT by placing the tablet between the upper gum and cheek above a molar tooth. Venous blood samples for measurement of plasma fentanyl concentrations were collected at regular intervals up to 8 hours following FBT administration. Parameters of interest included maximum plasma concentration (Cmax), time to reach Cmax (tmax), area under the plasma concentration-time curve from time zero to 8 hours (AUC8), and AUC from time zero to the median tmax (AUCtmax′). Adverse events were monitored throughout the study. Oral mucosal examinations and measurements of vital signs were performed at intervals up to 8 hours following FBT administration. Results: Sixteen patients, 8 with and 8 without oral mucositis, received FBT and completed the study. The severity of oral mucositis was mild in the patients exhibiting this condition. Median Cmax values were comparable: 1.14 ng/mL (range 0.26–2.69 ng/mL) in patients with mucositis, and 1.21 ng/mL (range 0.21–2.34 ng/mL) in patients without mucositis. The tmax was not significantly different in the two groups: median tmax was 25.0 min (range 15–45 min) in patients with mucositis and 22.5 min (range 10–121 min) in patients without mucositis. Median AUCtmax′ values were 0.17ng · h/mL (range 0.04–0.52 ng · h/ mL) in patients with mucositis, and 0.20 ng · h/mL (range 0.00–0.65 ng · h/mL) in patients without mucositis. The corresponding AUC8 values were 2.05 ng · h/mL (range 1.16–3.83 ng · h/mL) and 1.55 ng · h/mL (range 0.74–3.07 ng · h/ mL), respectively. FBT was generally well tolerated in this small group. No application site adverse events or changes in oral mucosal assessments were reported. Conclusion: The absorption profile of a single dose of FBT 200μg was similar in patients with or without mild oral mucositis. The compound was generally well tolerated.

Bioequivalence Following Buccal and Sublingual Placement of Fentanyl Buccal Tablet 400 μg in Healthy Subjects

Background and objective:The fentanyl buccal tablet (FBT) is formulated to enhance the rate and extent of fentanyl absorption across the buccal mucosa. FBT is indicated for the management of breakthrough pain (a transient flare of pain on a background of chronic pain otherwise controlled by treatment with opioids) in patients with cancer who are already receiving and who are tolerant to opioid therapy for their underlying persistent cancer pain. This study assessed the bioequivalence of a single 400-μg dose of FBT following buccal (i.e. above a molar tooth between the upper gum and cheek) and sublingual (i.e. placed under the tongue) placement in order to provide an alternative option to patients.Methods:Healthy subjects were randomized to receive one FBT 400 μg buccally and sublingually (with naltrexone to minimize opioid effects) in an open-label, crossover design. Bioequivalence, as determined from the maximum plasma drug concentration (Cmax) and the area under the plasma drug concentration-time curve from time 0 to infinity (AUC∞), was established if the 90% confidence interval (CI) for the ratio of the means of sublingual/buccal values fell within the range of 0.80 to 1.25.Results:Ninety subjects were enrolled (67 men, 23 women; median age 24 years), and 78 completed the study. The criteria for bioequivalence were met for both Cmax and AUC∞ for the two sites of tablet placement: sublingual/buccal ratio for Cmax = 0.868 (90% CI 0.815, 0.924); sublingual/buccal ratio for AUC∞ = 0.947 (90% CI 0.901, 0.995). Buccal and sublingual placement resulted in similar values for both AUC from time 0 to tmax′ (AUCtmax′), where tmax′ is the median time to Cmax of a single 400-μg dose of FBT administered buccally (mean [SD]: 0.35 [0.16] ng · h/mL buccal; 0.35 [0.16] ng · h/mL sublingual) and for time to Cmax (median [range]: 0.75 [0.33–3.13] hours buccal; 0.78 [0.17–3.00] hours sublingual). FBT was generally well tolerated following placement at both sites in healthy volunteers administered naltrexone.Conclusion:The results of this study support sublingual FBT placement as a viable alternative to buccal placement in patients who may require an alternate administration site.

Extent of Fentanyl Accumulation Following Multiple Doses of Fentanyl Buccal Tablet 400 µg 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 µg 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 (Cmax), time to Cmax (tmax), and area under the serum fentanyl concentration-time curve from 0 to 6 hours (AUC0–6) were summarized using descriptive statistics. Accumulation ratio was calculated as Cmax for dose 10/Cmax for dose 1, and was calculated similarly for AUC0–6. Results Fourteen volunteers (mean age 33 years) were enrolled, and 13 completed the study. After doses 1 and 10, respectively, mean (SD) Cmax was 1.70 (0.49) ng/mL and 1.97 (0.42) ng/mL, AUC0–6 was 4.46 (1.14) ng·h/mL and 6.81 (0.90) ng·h/mL, and median (range) tmax was 50 (30–110) minutes and 30 (15–120) minutes. Following 10 successive doses, systemic exposure (AUC0–6) was 55% higher than after dose 1, and Cmax 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% (AUC0–6) and 23% (Cmax) than after a single dose of FBT. Adverse events 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 µg in a randomized, open-label, crossover fashion. Naltrexone was given to minimize the opioid effects of fentanyl. Peak serum fentanyl concentration (Cmax), time to Cmax (tmax), area under the serum fentanyl concentration-time curve (AUC) from time 0 to infinity (AUC0–∞), and AUC from 0 to the last quantifiable concentration (AUC0–last) were summarized using descriptive statistics. Dose proportionality was claimed if the ln-ln plots of Cmax, AUC0–∞, and AUC0–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 Cmax, 1.0756 [1.0377, 1.1136] for AUC0–∞, and 1.0992 [1.0677, 1.1307] for AUC0–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 tmax 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.

535 COMPARATIVE BIOAVAILABILITY OF FENTANYL EFFERVESCENT BUCCAL TABLET (FEBT) AND ORAL TRANSMUCOSAL FENTANYL CITRATE (OTFC

Results: Supraespinose and paravertebral blocks were performed succesfully. Aditionally, he followed the therapy using an elastomeric pump with the following subcutaneous drugs: morphine 240mg/24h, midazolam 5mg/24h and metoclopramide 10mg/24h. He was also treated with oral pregabaline 75mg/12h, amitriptyline 10mg/12h and oral morphine 20mg as rescue analgesia. Although the treatment was effective, the patient asked for oral drugs after complaining of morfine intolerance. Opioid rotation was made. The new treatment included controlled-release oxycodone 60mg/12h and immediate-release oxycodone as rescue analgesia. Increasing the dosage was needed to control pain during the follow up. Conclusion: In cancer pain, oxycodone can be considered a valid alternative to oral morphine to be used for opioid rotation.