A possible solution to model nonlinearity in elimination and distributional clearances with α2 -adrenergic receptor agonists: Example of the intravenous detomidine and methadone combination in sedated horses.
Abstract: The alpha(α) -agonist detomidine is used for equine sedation with opioids such as methadone. We retrieved the data from two randomized, crossover studies where detomidine and methadone were given intravenously alone or combined as boli (STUDY 1) (Gozalo-Marcilla et al., 2017, Veterinary Anaesthesia and Analgesia, 2017, 44, 1116) or as 2-hr constant rate infusions (STUDY 2) (Gozalo-Marcilla et al., 2019, Equine Veterinary Journal, 51, 530). Plasma drug concentrations were measured with a validated tandem Mass Spectrometry assay. We used nonlinear mixed effect modelling and took pharmacokinetic (PK) data from both studies to fit simultaneously both drugs and explore their nonlinear kinetics. Two significant improvements over the classical mammillary two-compartment model were identified. First, the inclusion of an effect of detomidine plasma concentration on the elimination clearances (Cls) of both drugs improved the fit of detomidine (Objective Function Value [OFV]: -160) and methadone (OFV: -132) submodels. Second, a detomidine concentration-dependent reduction of distributional Cls of each drug further improved detomidine (OFV: -60) and methadone (OFV: -52) submodel fits. Using the PK data from both studies (a) helped exploring hypotheses on the nonlinearity of the elimination and distributional Cls and (b) allowed inclusion of dynamic effects of detomidine plasma concentration in the model which are compatible with the pharmacology of detomidine (vasoconstriction and reduction in cardiac output).
© 2019 John Wiley & Sons Ltd.
Publication Date: 2019-10-04 PubMed ID: 31584710DOI: 10.1111/jvp.12815Google Scholar: Lookup
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- Journal Article
Summary
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The research discusses how the combined usage of drugs detomidine and methadone in sedated horses affects their elimination and distribution, using two differently structured studies for data. The researchers found an association between higher plasma detomidine concentration and improved elimination of both drugs. They also detected a detomidine concentration-dependent reduction in distribution clearances for each drug.
Methodology
- Data for the research was drawn from two randomised, crossover studies. In both studies, detomidine and methadone were administered intravenously. The method of administration varied, with the drugs being given as boluses in the first study and as a 2-hour constant rate infusion in the second study.
- Plasma drug concentrations were determined using a validated tandem Mass Spectrometry assay, a technique that accurately measures the concentration of specific molecules.
- Nonlinear mixed effect modelling was used to analyse the pharmacokinetic (PK) data from both studies. Through this, researchers could explore the nonlinear kinetics of the drugs when given in combination.
Key Findings
- The research found that detomidine’s plasma concentration impacts the elimination clearances of both detomidine and methadone, showing an improvement with the increase in concentration. This finding improved the model fit for both drug submodels. Elimination clearance is a measurement of the volume of plasma from which a substance is completely removed per unit time.
- A detomidine concentration-dependent decrease was observed in the distribution clearances of each drug. Distribution clearance refers to the rate at which a drug leaves the bloodstream and enters the body tissue. This also improved the fit of both drug submodels.
- Integrating the PK data from both studies allowed for an exploration of hypotheses regarding the nonlinearity of elimination and distribution clearances of the drugs. It also permitted the inclusion of dynamic effects of detomidine plasma concentration in the model, aligning with its known pharmacological effects such as vasoconstriction and reduction in cardiac output.
Cite This Article
APA
Gozalo-Marcilla M, Moreira da Silva R, Pacca Loureiro Luna S, Rodrigues de Oliveira A, Werneck Fonseca M, Peporine Lopes N, Taylor PM, Pelligand L.
(2019).
A possible solution to model nonlinearity in elimination and distributional clearances with α2 -adrenergic receptor agonists: Example of the intravenous detomidine and methadone combination in sedated horses.
J Vet Pharmacol Ther, 42(6), 738-744.
https://doi.org/10.1111/jvp.12815 Publication
Researcher Affiliations
- The Royal (Dick) School of Veterinary Studies and the Roslin Institute, The University of Edinburgh, Midlothian, UK.
- Núcleo de Pesquisas em Produtos Naturais e Sintéticos (NPPNS), School of Pharmaceutical Sciences, University of São Paulo (USP), Ribeirão Preto, Brazil.
- São Paulo State University (UNESP), School of Veterinary Medicine and Animal Science, Botucatu, Brazil.
- São Paulo State University (UNESP), School of Veterinary Medicine and Animal Science, Botucatu, Brazil.
- São Paulo State University (UNESP), School of Veterinary Medicine and Animal Science, Botucatu, Brazil.
- Núcleo de Pesquisas em Produtos Naturais e Sintéticos (NPPNS), School of Pharmaceutical Sciences, University of São Paulo (USP), Ribeirão Preto, Brazil.
- Taylor Monroe, Ely, UK.
- Royal Veterinary College, Hatfield, UK.
MeSH Terms
- Adrenergic alpha-2 Receptor Agonists / administration & dosage
- Adrenergic alpha-2 Receptor Agonists / pharmacokinetics
- Analgesics, Opioid / pharmacokinetics
- Animals
- Drug Combinations
- Horses
- Imidazoles / administration & dosage
- Imidazoles / pharmacokinetics
- Methadone / administration & dosage
- Methadone / pharmacokinetics
- Tissue Distribution
Grant Funding
- 2010/08967-0 / Fundau00e7u00e3o de Amparo u00e0 Pesquisa do Estado de Su00e3o Paulo
- 2014/00474-5 / Fundau00e7u00e3o de Amparo u00e0 Pesquisa do Estado de Su00e3o Paulo
- 2014/50265-3 / Fundau00e7u00e3o de Amparo u00e0 Pesquisa do Estado de Su00e3o Paulo
- 2017/01425-6 / Fundau00e7u00e3o de Amparo u00e0 Pesquisa do Estado de Su00e3o Paulo
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This article includes 19 references
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Citations
This article has been cited 2 times.- Haunhorst FR, Hopster K, Schmicke M, Bienert-Zeit A, Kästner S. Clinical effect of buprenorphine or butorphanol, in combination with detomidine and diazepam, on sedation and postoperative pain after cheek tooth extraction in horses.. Can Vet J 2022 Jan;63(1):39-46.
- de Oliveira AR, Gozalo-Marcilla M, Ringer SK, Schauvliege S, Fonseca MW, Esteves Trindade PH, Prospero Puoli Filho JN, Luna SPL. Development and validation of the facial scale (FaceSed) to evaluate sedation in horses.. PLoS One 2021;16(6):e0251909.
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