PMID- 26804639
OWN - NLM
STAT- MEDLINE
DCOM- 20161007
LR  - 20181202
IS  - 1879-114X (Electronic)
IS  - 0149-2918 (Linking)
VI  - 38
IP  - 2
DP  - 2016 Feb
TI  - Evaluation of the Pharmacokinetics of Single- and Multiple-dose Buprenorphine 
      Buccal Film in Healthy Volunteers.
PG  - 358-69
LID - S0149-2918(15)01376-4 [pii]
LID - 10.1016/j.clinthera.2015.12.016 [doi]
AB  - PURPOSE: Buprenorphine, a partial mu-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 mug) of 2 
      formulations (F14 and F24) of buccal buprenorphine (BBUP) and a 300-mug 
      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 mug 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. FINDINGS: 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-microg dose to 
      1.43 ng/mL for the 1200-microg dose. AUC0-infinity, 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 mug BID. 
      Treatment-emergent AEs in both studies were consistent with those reported with 
      opiate administration to healthy volunteers. IMPLICATIONS: 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.
CI  - Copyright (c) 2016 Elsevier HS Journals, Inc. All rights reserved.
FAU - Bai, Stephen A
AU  - Bai SA
AD  - Endo Pharmaceuticals Inc., Malvern, Pennsylvania.
FAU - Xiang, Qinfang
AU  - Xiang Q
AD  - Endo Pharmaceuticals Inc., Malvern, Pennsylvania. Electronic address: 
      xiang.qinfang@endo.com.
FAU - Finn, Andrew
AU  - Finn A
AD  - BioDelivery Sciences International Inc., Raleigh, North Carolina.
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
PT  - Research Support, Non-U.S. Gov't
DEP - 20160121
PL  - United States
TA  - Clin Ther
JT  - Clinical therapeutics
JID - 7706726
RN  - 0 (Analgesics, Opioid)
RN  - 40D3SCR4GZ (Buprenorphine)
RN  - 7E53B4O073 (norbuprenorphine)
SB  - IM
MH  - Adult
MH  - Analgesics, Opioid/administration & dosage/*pharmacokinetics
MH  - Biological Availability
MH  - Buprenorphine/administration & dosage/*analogs & derivatives/*pharmacokinetics
MH  - Chemistry, Pharmaceutical
MH  - Cross-Over Studies
MH  - Female
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Pain/drug therapy
MH  - Young Adult
OTO - NOTNLM
OT  - bioavailability
OT  - buprenorphine buccal film
OT  - pharmacokinetics
EDAT- 2016/01/26 06:00
MHDA- 2016/10/08 06:00
CRDT- 2016/01/26 06:00
PHST- 2015/10/30 00:00 [received]
PHST- 2015/12/29 00:00 [revised]
PHST- 2015/12/30 00:00 [accepted]
PHST- 2016/01/26 06:00 [entrez]
PHST- 2016/01/26 06:00 [pubmed]
PHST- 2016/10/08 06:00 [medline]
AID - S0149-2918(15)01376-4 [pii]
AID - 10.1016/j.clinthera.2015.12.016 [doi]
PST - ppublish
SO  - Clin Ther. 2016 Feb;38(2):358-69. doi: 10.1016/j.clinthera.2015.12.016. Epub 2016 
      Jan 21.