title: Evaluation of the Pharmacokinetics of Single- and Multiple-dose Buprenorphine Buccal Film in Healthy Volunteers.
abstract: OBJECTIVE
  Buprenorphine, a partial μ-receptor agonist, is approved for the management of moderate to severe pain, but it has low oral bioavailability. Two open-label studies were performed to determine the pharmacokinetic profile of buprenorphine from buccal film formulations of buprenorphine.
  
  
  METHODS
  Both studies enrolled healthy volunteers, aged 18 to 55 years, who received concurrent oral naltrexone to reduce adverse events (AEs); subjects with a history or evidence of substance abuse or current use of any product affecting cytochrome P450 3A4 activity were excluded. The first study (n = 25) was a 5-period crossover trial with 4 single doses (75 and 300 and 300 and 1200 μg) of 2 formulations (F14 and F24) of buccal buprenorphine (BBUP) and a 300-μg intravenous dose of buprenorphine with a 7-day washout between periods. In the second study, each subject (n = 10) received 6 doses of 4 BBUP strengths (60, 120, 180, and 240 μg BID) in a dose-escalation design. Plasma concentrations of buprenorphine and norbuprenorphine were assayed, and pharmacokinetics were summarized with descriptive statistics and analyzed by using a linear mixed effects model (single-dose study). AEs were recorded.
  
  
  RESULTS
  In the single-dose study, the 2 formulations exhibited comparable bioavailability of 46% to 51% that was independent of dose, with a single buprenorphine peak concentration from each BBUP dose occurring at 2.5 to 3 hours. The mean buprenorphine Cmax across the doses ranged from 0.17 ng/mL for the 75-µg dose to 1.43 ng/mL for the 1200-µg dose. AUC0-∞, AUC0-last, and Cmax were proportional to the dose of BBUP administered. Cmax of norbuprenorphine after BBUP administration was approximately one tenth that of buprenorphine Cmax. In the multiple-dose study, steady state was reached within 3 days of BID dosing. There was a linear increase in exposure across the dose range from 60 to 240 μg BID. Treatment-emergent AEs in both studies were consistent with those reported with opiate administration to healthy volunteers.
  
  
  CONCLUSIONS
  The absolute bioavailability of BBUP was 46% to 51% across a 16-fold dose range, with dose-proportional increases in systemic exposure. Apparent steady-state conditions occurred within 3 days of dosing. These pharmacokinetic results suggest that therapeutic buprenorphine plasma concentrations can be obtained with BBUP across a wide dose range in a shorter time than other (eg, transdermal) dosage forms.
authors.affiliation: Endo Pharmaceuticals Inc., Malvern, Pennsylvania.
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Bai
authors.affiliation: Endo Pharmaceuticals Inc., Malvern, Pennsylvania. Electronic address: xiang.qinfang@endo.com.
authors.forename: Qinfang
authors.initials: Q
authors.lastname: Xiang
authors.affiliation: BioDelivery Sciences International Inc., Raleigh, North Carolina.
authors.forename: Andrew
authors.initials: A
authors.lastname: Finn
mesh_terms: D000328:Adult; D000701:Analgesics, Opioid / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001682:Biological Availability; D002047:Buprenorphine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics*; D002626:Chemistry, Pharmaceutical; D018592:Cross-Over Studies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010146:Pain / Q000188:drug therapy; D055815:Young Adult
chemical_list: D000701:Analgesics, Opioid; D002047:Buprenorphine; C043585:norbuprenorphine
keywords: bioavailability; buprenorphine buccal film; pharmacokinetics