Bioequivalence Following Buccal and Sublingual Placement of Fentanyl Buccal Tablet 400 μg in Healthy Subjects
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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.
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.
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.
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.
KeywordsFentanyl Naltrexone Breakthrough Pain Fentanyl Buccal Tablet Median Tmax
This study was sponsored by Cephalon, Inc. (Frazer, PA, USA). The authors are employed by the sponsoring company. The authors would like to thank the investigator (Alan S. Marion, MD, CCTI, of MDS Pharma Services, Lincoln, NE, USA) and the subjects who participated in this study. Writing assistance was provided by Embryon.
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