title: Formulation selection and pharmacokinetic comparison of fentanyl buccal soluble film with oral transmucosal fentanyl citrate: a randomized, open-label, single-dose, crossover study.
abstract: OBJECTIVE
  BioErodible MucoAdhesive (BEMA) is a new transmucosal drug delivery system designed to improve and ease the administration of drugs by this route. The first product that uses this novel delivery system contains fentanyl and is intended for the treatment of breakthrough pain in opioid-tolerant patients with cancer. The generic name is fentanyl buccal soluble film (FBSF). The objectives of this study were to compare the pharmacokinetic profile of FBSF formulations at three different pHs (pH 6, pH 7.25 and pH 8.5) and to understand the differences in the pharmacokinetics of fentanyl from FBSF compared with that of oral transmucosal fentanyl citrate (OTFC).
  
  
  METHODS
  This was a randomized, open-label, single-dose, four-period, Latin-square crossover study consisting of a 9-day inpatient treatment period. The study was conducted at a phase 1 clinical research unit in Austin, TX, USA. Twelve healthy subjects were enrolled, nine males and three females, between the ages of 21 and 44 years. Each subject received four 800 microg doses of fentanyl: single doses of the three FBSF formulations (pH 6, pH 7.25 and pH 8.5) and OTFC, with concurrent naltrexone. Plasma fentanyl concentrations were measured over a 48-hour period after each study dose. Pharmacokinetic parameters were calculated and compared.
  
  
  RESULTS
  Peak plasma fentanyl concentrations (Cmax) and overall fentanyl systemic exposure (area under the plasma concentration-time curve from time zero extrapolated to infinity [AUCinfinity]) for each of the three FBSF formulations were greater than for OTFC. The pH 7.25 FBSF formulation provided the earliest time to reach Cmax (tmax), the highest Cmax value and the greatest AUC(infinity) value. Compared with OTFC, peak plasma fentanyl concentrations with pH 7.25 FBSF were significantly higher (mean Cmax 1.67 vs 1.03 ng/mL; p<0.05). Overall exposure was also greater with pH 7.25 FBSF than with OTFC (mean AUCinfinity 14.5 vs 10.3 ng . h/mL).
  
  
  CONCLUSIONS
  All three FBSF formulations produced greater peak plasma concentrations and overall exposure to fentanyl than OTFC. In particular, the pH 7.25 FBSF formulation showed the most favourable pharmacokinetic profile of the three FBSF formulations. In comparison with OTFC, the pH 7.25 FBSF formulation produced the fastest and most efficient fentanyl delivery and was selected for further clinical development.
authors.affiliation: BioDelivery Sciences International, Inc., Raleigh, North Carolina 27607, USA.
authors.forename: Niraj
authors.initials: N
authors.lastname: Vasisht
authors.forename: Larry N
authors.initials: LN
authors.lastname: Gever
authors.forename: Ignacio
authors.initials: I
authors.lastname: Tagarro
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Finn
mesh_terms: D000269:Adhesives; D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D019540:Area Under Curve; D002138:Calibration; D002610:Cheek; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D004311:Double-Blind Method; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage* / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D009061:Mouth Mucosa; D012015:Reference Standards; D055815:Young Adult
chemical_list: D000269:Adhesives; D000701:Analgesics, Opioid; D005283:Fentanyl