• Mona Darwish, Mary Kirby, Philmore Robertson, William Tracewell, and John G Jiang.
• Department of Clinical Pharmacology, Cephalon, Inc., Frazer, Pennsylvania 19355, USA. mdarwish@cephalon.com
• Clin Ther. 2006 May 1;28(5):707-14.

BackgroundThe fentanyl effervescent buccal tablet (FEBT) is designed to enhance the rate and extent of the absorption of fentanyl, an opioid, through the buccal mucosa.ObjectivesThe purposes of this study were to assess the dose proportionality of FEBT in healthy volunteers over the potential therapeutic dose range (100-800 microg) and characterize the pharmacokinetic (PK) profile of 4 doses (100, 200, 400, and 800 microg) of FEBT.MethodsThis Phase I, randomized, open-label, 4-period crossover study was conducted at Radiant Research, Honolulu, Hawaii. Healthy adult volunteers with intolerance to opioids were randomly assigned to receive 1 of 4 single-dose sequences of FEBT: 100, 200, 400, and 800 microg (selected to encompass the anticipated therapeutic dose range), with each successive administration separated by a washout period of >or=7 days. Naltrexone hydrochloride (50-mg tablet) was administered-15 and 3 hours before and 9 hours after FEBT administration to block opioid receptor-mediated effects of fentanyl. Plasma fentanyl concentrations were measured from venous samples obtained over 72 hours after FEBT administration. Early fentanyl exposure was assessed using AUC from time 0 to 0.75 hour (the median T(max) of the reference dose [100 microg]) (AUC(0-Tmax')). Adverse events (AEs) were monitored and recorded throughout the study by medically qualified personnel.ResultsThirty-two subjects (26 men, 6 women; mean [SD] age, 29.3 [7.2] years [range, 19-44 years]; mean [SD] weight, 74.7 [10.7] kg) were enrolled. Median T was between 35 and 45 minutes after FEBT administration. AUC(0-infinity) and C(max) increased approximately linearly with increasing doses of FEBT. Mean plasma fentanyl concentrations decreased from C(max) in a biexponential manner at the 100- and 200-microg doses and decreased in a triexponential manner at the 800-mug dose. Despite the triexponential decrease in the mean profile observed with the 400-microg dose, a biexponential decrease was observed in approximately half of the individual profiles. AUC(0-Tmax') ranged from 0.09 ng x h/mL with the 100-microg dose to 0.52 ng x h/mL with the 800-microg dose. The most commonly reported AEs in the 100-, 200-, 400-, and 800-microg dose groups were as follows: application-site erythema, 3, 3, 4, and 3 subjects, respectively; nausea, 3, 2, 5, and 4 subjects; somnolence, 3, 2, 3, and 2 subjects; and headache, 3, 2, 1, and 4 subjects. None of the AEs were serious.ConclusionsIn this study of the dose proportionality of FEBT in healthy volunteers, the PK profile of FEBT was characterized by a high early systemic exposure of fentanyl (0.09-0.52 ng x h/mL). Dose-dependent parameters (C(max) and AUC) increased in an approximately dose-proportional manner from 100 to 800 microg FEBT.

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