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


CONCLUSIONS
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.
Darwish
Mona
M
Clinical Pharmacology, Cephalon, Inc., Frazer, PA, USA. mdarwish@cephalon.com
Tempero
Kenneth
K
Kirby
Mary
M
Thompson
Jeffrey
J
D000278:Administration, Buccal; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D018592:Cross-Over Studies; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage* / Q000009:adverse effects / Q000097:blood / Q000493:pharmacokinetics*; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D013607:Tablets
D000701:Analgesics, Opioid; D013607:Tablets; D005283:Fentanyl