Characterisation of the in vivo interactions between detomidine and methadone in horses: Pharmacokinetic and pharmacodynamic modelling.
alpha 2 agonist
horse
nociceptive threshold
opioid
sedation
synergism
Journal
Equine veterinary journal
ISSN: 2042-3306
Titre abrégé: Equine Vet J
Pays: United States
ID NLM: 0173320
Informations de publication
Date de publication:
Jul 2019
Jul 2019
Historique:
received:
06
03
2018
accepted:
24
09
2018
pubmed:
10
10
2018
medline:
13
11
2019
entrez:
10
10
2018
Statut:
ppublish
Résumé
Pharmacokinetic (PK)/pharmacodynamic (PD) modelling offers new insights to design protocols for sedation and analgesia in standing horses. To evaluate the parameters and interactions between detomidine and methadone when given alone or combined in standing horses. Randomised, placebo-controlled, blinded, crossover. Eight adult healthy horses were given six treatments intravenously: saline (SAL); detomidine (5 μg/kg bwt; DET); methadone (0.2 mg/kg bwt; MET) alone or combined with detomidine (2.5 [MLD], 5 [MMD] or 10 [MHD] μg/kg bwt). Venous blood samples were obtained at predetermined times between 0 and 360 min after drug administration. Plasma detomidine and methadone were measured using a single, liquid/liquid extraction technique by liquid chromatography coupled with a triple quadrupole mass spectrometer (LC-MS/MS). Sequential PK/PD modelling compared rival models, with and without PK and PD interaction between drugs, to fit the PD data including height of the head above the ground (HHAG), a visual analogue scale for sedation (VAS), electrical (ET), thermal (TT) and mechanical (MT) nociceptive thresholds and gastrointestinal motility (GIM) [1]. Two and three compartment models best described the PK of detomidine and methadone, respectively. Detomidine decreased its own clearance as well as the clearance of methadone. The interaction of methadone on the effect of detomidine revealed an infra-additive (partial antagonism) effect for HHAG (α = -1.33), VAS (α = -0.98) and GIM (α = -1.05), a positive potentiation for ET (pot = 0.0041) and TT (pot = 0.133) and a synergistic to additive effect for MT (α = 0.78). This is a small experimental study. Different PK/PD interactions were demonstrated for each PD parameter and could be modelled in vivo. The modelling of our data will allow us to simulate and predict the effect of constant rate infusions of both drugs for future investigations.
Sections du résumé
BACKGROUND
BACKGROUND
Pharmacokinetic (PK)/pharmacodynamic (PD) modelling offers new insights to design protocols for sedation and analgesia in standing horses.
OBJECTIVES
OBJECTIVE
To evaluate the parameters and interactions between detomidine and methadone when given alone or combined in standing horses.
STUDY DESIGN
METHODS
Randomised, placebo-controlled, blinded, crossover.
METHODS
METHODS
Eight adult healthy horses were given six treatments intravenously: saline (SAL); detomidine (5 μg/kg bwt; DET); methadone (0.2 mg/kg bwt; MET) alone or combined with detomidine (2.5 [MLD], 5 [MMD] or 10 [MHD] μg/kg bwt). Venous blood samples were obtained at predetermined times between 0 and 360 min after drug administration. Plasma detomidine and methadone were measured using a single, liquid/liquid extraction technique by liquid chromatography coupled with a triple quadrupole mass spectrometer (LC-MS/MS). Sequential PK/PD modelling compared rival models, with and without PK and PD interaction between drugs, to fit the PD data including height of the head above the ground (HHAG), a visual analogue scale for sedation (VAS), electrical (ET), thermal (TT) and mechanical (MT) nociceptive thresholds and gastrointestinal motility (GIM) [1].
RESULTS
RESULTS
Two and three compartment models best described the PK of detomidine and methadone, respectively. Detomidine decreased its own clearance as well as the clearance of methadone. The interaction of methadone on the effect of detomidine revealed an infra-additive (partial antagonism) effect for HHAG (α = -1.33), VAS (α = -0.98) and GIM (α = -1.05), a positive potentiation for ET (pot = 0.0041) and TT (pot = 0.133) and a synergistic to additive effect for MT (α = 0.78).
MAIN LIMITATIONS
CONCLUSIONS
This is a small experimental study.
CONCLUSIONS
CONCLUSIONS
Different PK/PD interactions were demonstrated for each PD parameter and could be modelled in vivo. The modelling of our data will allow us to simulate and predict the effect of constant rate infusions of both drugs for future investigations.
Substances chimiques
Analgesics, Opioid
0
Hypnotics and Sedatives
0
Imidazoles
0
detomidine
7N8K34P2XH
Methadone
UC6VBE7V1Z
Types de publication
Clinical Trial, Veterinary
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
517-529Subventions
Organisme : Fundação de Amparo à Pesquisa do Estado de São Paulo
ID : 2010/08967-0
Organisme : Fundação de Amparo à Pesquisa do Estado de São Paulo
ID : 2014/00474-5
Organisme : Fundação de Amparo à Pesquisa do Estado de São Paulo
ID : 2014/50265-3
Organisme : Fundação de Amparo à Pesquisa do Estado de São Paulo
ID : 2017/01425-6
Informations de copyright
© 2018 EVJ Ltd.