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 1080 mu g. 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 (t(max)) 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 500 mu g doses and a triexponential decline after FEBT 810 and 1080 mu g doses. The maximum serum concentration (C-max) of fentanyl was proportional up to and including the 810 mu g dose. The increase in Cmax was 20% less than proportional at the 1080 mu g dose. Systemic exposure to fentanyl, as measured by the area under the serum concentration-time curve from time zero to infinity (AUC(infinity)), increased proportionally with increasing doses of FEBT (200-1080 mu g). 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 AUC(infinity) of FEBT increased in a dose-proportional manner from 200 to 810 mu g. This study provides preliminary, pharmacokinetic data for FEBT across the potential therapeutic dose range.