title: Relative bioavailability of the fentanyl effervescent buccal tablet (FEBT) 1,080 pg versus oral transmucosal fentanyl citrate 1,600 pg and dose proportionality of FEBT 270 to 1,300 microg: a single-dose, randomized, open-label, three-period study in healthy adult volunteers.
abstract: BACKGROUND
  The fentanyl effervescent buccal tablet (FEBT) was designed to enhance the rate and extent of absorption of fentanyl through the buccal mucosa. FEBT is being investigated for the management of breakthrough pain.
  
  
  OBJECTIVE
  The primary objective of this study was to compare the relative bioavailability of FEBT 1,080 microg with that of oral transmucosal fentanyl citrate (OTFC) 1,600 microg, and the secondary objective was to assess the dose proportionality of FEBT 270 to 1,300 microg in healthy adult volunteers.
  
  
  METHODS
  This single-dose, randomized, open-label, 3-period study was conducted by MDS Pharma Services, Lincoln, Nebraska. Non-opioid-tolerant healthy adult volunteers were included. In periods 1 and 2 (relative-bioavailability analysis), subjects were randomly assigned to 1 of 2 administration sequences: single-dose FEBT 1,080 microg followed by single-dose OTFC 1,600 microg, or vice versa; in period 3 (dose-proportionality analysis), they were randomly assigned to receive a single dose of FEBT 270, 810, or 1,300 microg. Subjects were instructed to place FEBT between the gum and cheek above an upper molar tooth and allow it to disintegrate for 10 minutes. Subjects were instructed to place the OTFC lozenge between the cheek and lower gum and move the unit from side to side using the handle and allow the unit to dissolve for 15 minutes. All subjects received naltrexone 50 mg PO at 15 and 3 hours before and 12 hours after fentanyl administration, except those receiving FEBT 270 microg, who were not given naltrexone at 12 hours. For the measurement of serum concentrations of fentanyl, venous blood samples were collected before and up to 36 hours after study drug administration. For tolerability analysis, continuous pulse oximetry, 12-lead electrocardiography, clinical laboratory analysis, and physical examination, including vital-sign measurements, were performed; the oral mucosa was inspected; and spontaneous reporting was employed.
  
  
  RESULTS
  A total of 42 subjects were enrolled (25 women, 17 men; mean [SD] age, 27 [11] years; mean [SD] weight, 68.4 [8.7] kg); 39 completed the study. Total systemic exposure (as measured using AUC(0-infinity))) was statistically similar between FEBT 1,080 microg and OTFC 1,600 microg (mean [SD], 18.0 [5.4] vs 18.0 [7.1] ng x h/mL). However, the mean (SD) C(max) with FEBT 1,080 microg was 2.7 (0.9) ng/mL compared with 2.2 (0.7) ng/mL with OTFC 1,600 microg (P = NS), and the T(max) of 1.0 hour with FEBT was significantly less compared with OTFC (2.0 hours; P < 0.001). Similarly, mean (SD) early systemic exposure (AUC(0-Tmax'); ie, AUC from time 0 to 1 hour the median T(max) of the reference dose of FEBT [810 microg]) was significantly greater with FEBT compared with OTFC (1.5 [0.5] vs 0.8 [0.4] ng x h/mL; P < 0.001). Exploratory analyses suggested dose proportionality as assessed using AUC(0-infinity) and AUC(0-Tmax') over the range of FEBT 270 to 1,300 microg. Increases in C(max) were less than dose proportional at FEBT doses >810 microg. Definitive attribution of adverse events (AEs) to FEBT or OTFC was generally not possible because these medications were coadministered with naltrexone. With naltrexone alone, there were reports of headache (3 [7%] subjects), nausea (1 [2%]), upset stomach (1 [2%]), and low systolic blood pressure (1 [2%]) after naltrexone administration, but before FEBT or OTFC administration. The AEs were typical of opioids (ie, headache, nausea, lightheadedness), and most (89.6%) were mild. One case each of mild oral irritation and redness were reported after the administration of FEBT Both occurrences resolved within 4.5 hours after study drug administration. No irritation or redness was reported after the administration of OTFC.
  
  
  CONCLUSIONS
  In this pharmacokinetic study in healthy volunteers, total systemic exposure increased in a dose-proportional manner up to FEBT 1,300 microg, whereas doses above 810 microg showed a less-than-dose-proportional increase in C(max). The results suggest that fentanyl enters the systemic circulation to a significantly greater extent (C(max) and AUC(0-Tmax')) and significantly more rapidly (T(max)) with FEBT compared with OTFC.
authors.affiliation: Cephalon, Inc., Frazer, Pennsylvania 19355, USA. mdarwish@cephlon.com
authors.forename: Mona
authors.initials: M
authors.lastname: Darwish
authors.forename: Kenneth
authors.initials: K
authors.lastname: Tempero
authors.forename: Mary
authors.initials: M
authors.lastname: Kirby
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Thompson
mesh_terms: D000278:Administration, Buccal; D000284:Administration, Oral; D000328:Adult; D000465:Algorithms; D000701:Analgesics, Opioid / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D019540:Area Under Curve; D001682:Biological Availability; D004305:Dose-Response Relationship, Drug; D005260:Female; D005283:Fentanyl / Q000008:administration & dosage* / Q000097:blood / Q000493:pharmacokinetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009329:Nebraska; D010146:Pain / Q000188:drug therapy; D013997:Time Factors
chemical_list: D000701:Analgesics, Opioid; D005283:Fentanyl