PMID- 28445495
OWN - NLM
STAT- MEDLINE
DCOM- 20170907
LR  - 20220321
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 12
IP  - 4
DP  - 2017
TI  - Pharmacokinetic and pharmacodynamic modelling after subcutaneous, intravenous and 
      buccal administration of a high-concentration formulation of buprenorphine in 
      conscious cats.
PG  - e0176443
LID - 10.1371/journal.pone.0176443 [doi]
LID - e0176443
AB  - BACKGROUND: The aim of this study was to describe the joint 
      pharmacokinetic-pharmacodynamic model and evaluate thermal antinociception of a 
      high-concentration formulation of buprenorphine (Simbadol) in cats. METHODS: Six 
      healthy cats (4.9 +/- 0.7 kg) were included in a prospective, randomized, blinded, 
      crossover study. Simbadol (1.8 mg mL-1) was administered by the subcutaneous 
      (SC; 0.24 mg kg-1), intravenous (IV; 0.12 mg kg-1) or buccal (OTM; 0.12 mg kg-1) 
      route of administration and thermal thresholds (TT) were compared with a saline 
      group (SAL). Thermal threshold testing and blood sampling were performed at 
      predetermined time points up to 72 hours including a placebo group. Plasma 
      buprenorphine and norbuprenorphine concentrations were measured using liquid 
      chromatography mass spectrometry. A bespoke bicompartmental pharmacokinetic model 
      simultaneously fitted data from two analytes/three routes of administration. 
      Temporal changes in TT were analyzed using one-way ANOVA followed by Dunnett's 
      test and treatment comparisons using two-way ANOVA with Bonferroni's correction 
      (P < 0.05). RESULTS: Thermal thresholds were significantly increased after SC, IV 
      and OTM from 1-24 hours (except 2 hours), 0.5-8 hours (except 6 hours), and 1-8 
      hours (except 6 hours), respectively, when compared with baseline. Thermal 
      thresholds were significantly increased after SC (1-30 hours), IV (1-8 hours) and 
      OTM (1-12 hours) when compared with SAL, but not different among 
      buprenorphine-treated cats. The absolute buprenorphine clearance was 0.98 L kg-1 
      hour-1, volume of distribution at steady state was 7.9 L kg-1 and the 
      elimination-half-life was 12.3 hours. Bioavailability for SC and OTM was 94% and 
      24%, respectively. Subcutaneous absorption was biphasic. An initial peak (0.08 
      hours) was followed by a slow (half-life 11.2 hours) and progressive (peak 
      acceleration at 2.8 hours) uptake. CONCLUSION: The SC administration of Simbadol 
      was characterized by prolonged absorption half-life and sustained plasma 
      concentrations yielding long-lasting antinociception (>/= 24 hours) when compared 
      with the IV and OTM routes.
FAU - Doodnaught, Graeme M
AU  - Doodnaught GM
AD  - Departement de Sciences Cliniques, Faculte de Medecine Veterinaire, Universite de 
      Montreal, Saint-Hyacinthe, Quebec, Canada.
FAU - Monteiro, Beatriz P
AU  - Monteiro BP
AD  - Groupe de Recherche en Pharmacologie Animal du Quebec (GREPAQ), Departement de 
      Biomedecine Veterinaire, Faculte de Medecine Veterinaire, Universite de Montreal, 
      St-Hyacinthe, Quebec, Canada.
FAU - Benito, Javier
AU  - Benito J
AD  - Departement de Sciences Cliniques, Faculte de Medecine Veterinaire, Universite de 
      Montreal, Saint-Hyacinthe, Quebec, Canada.
FAU - Edge, Daniel
AU  - Edge D
AD  - Zoetis Inc., Florham Park, New Jersey, United States of America.
FAU - Beaudry, Francis
AU  - Beaudry F
AD  - Groupe de Recherche en Pharmacologie Animal du Quebec (GREPAQ), Departement de 
      Biomedecine Veterinaire, Faculte de Medecine Veterinaire, Universite de Montreal, 
      St-Hyacinthe, Quebec, Canada.
FAU - Pelligand, Ludovic
AU  - Pelligand L
AD  - Department of Clinical Sciences and Services, The Royal Veterinary College, North 
      Mymms, Hertfordshire, United Kingdom.
FAU - Steagall, Paulo
AU  - Steagall P
AUID- ORCID: 0000-0003-4150-6043
AD  - Departement de Sciences Cliniques, Faculte de Medecine Veterinaire, Universite de 
      Montreal, Saint-Hyacinthe, Quebec, Canada.
AD  - Groupe de Recherche en Pharmacologie Animal du Quebec (GREPAQ), Departement de 
      Biomedecine Veterinaire, Faculte de Medecine Veterinaire, Universite de Montreal, 
      St-Hyacinthe, Quebec, Canada.
LA  - eng
PT  - Journal Article
PT  - Randomized Controlled Trial
DEP - 20170426
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Analgesics, Opioid)
RN  - 40D3SCR4GZ (Buprenorphine)
RN  - 7E53B4O073 (norbuprenorphine)
SB  - IM
MH  - Administration, Buccal
MH  - Analgesics, Opioid/blood/*pharmacokinetics/pharmacology
MH  - Animals
MH  - Biological Availability
MH  - Buprenorphine/analogs & derivatives/blood/*pharmacokinetics/pharmacology
MH  - Cats
MH  - Cross-Over Studies
MH  - Disease Models, Animal
MH  - Female
MH  - Half-Life
MH  - Injections, Intravenous
MH  - Injections, Subcutaneous
MH  - Male
MH  - *Models, Biological
MH  - Pain/*prevention & control
MH  - Pain Threshold/drug effects
MH  - Placebo Effect
MH  - Prospective Studies
MH  - Time Factors
PMC - PMC5405979
COIS- Competing Interests: Dr. Paulo Steagall has received speaker honoraria and 
      provided consultancy services to Zoetis. Dr. Beatriz Monteiro has provided 
      consultancy services for Zoetis. Dr. Ludovic Pelligand has received honoraria and 
      provided consultancy services to Zoetis. Dr. Daniel Edge is an employee of 
      Zoetis. This does not alter the authors' adherence to PLOS ONE policies on 
      sharing data and materials.
EDAT- 2017/04/27 06:00
MHDA- 2017/09/08 06:00
PMCR- 2017/04/26
CRDT- 2017/04/27 06:00
PHST- 2016/12/23 00:00 [received]
PHST- 2017/04/10 00:00 [accepted]
PHST- 2017/04/27 06:00 [entrez]
PHST- 2017/04/27 06:00 [pubmed]
PHST- 2017/09/08 06:00 [medline]
PHST- 2017/04/26 00:00 [pmc-release]
AID - PONE-D-16-49428 [pii]
AID - 10.1371/journal.pone.0176443 [doi]
PST - epublish
SO  - PLoS One. 2017 Apr 26;12(4):e0176443. doi: 10.1371/journal.pone.0176443. 
      eCollection 2017.