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Population Modelling of Dexmedetomidine Pharmacokinetics and Haemodynamic Effects After Intravenous and Subcutaneous Administration

BACKGROUND AND OBJECTIVE: Dexmedetomidine is a potent agonist of α(2)-adrenoceptors causing dose-dependent sedation in humans. Intravenous dexmedetomidine is commonly used perioperatively, but an extravascular route of administration would be favoured in palliative care. Subcutaneous infusions provi...

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Autores principales: Ashraf, Muhammad W., Uusalo, Panu, Scheinin, Mika, Saari, Teijo I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658092/
https://www.ncbi.nlm.nih.gov/pubmed/32462542
http://dx.doi.org/10.1007/s40262-020-00900-3
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author Ashraf, Muhammad W.
Uusalo, Panu
Scheinin, Mika
Saari, Teijo I.
author_facet Ashraf, Muhammad W.
Uusalo, Panu
Scheinin, Mika
Saari, Teijo I.
author_sort Ashraf, Muhammad W.
collection PubMed
description BACKGROUND AND OBJECTIVE: Dexmedetomidine is a potent agonist of α(2)-adrenoceptors causing dose-dependent sedation in humans. Intravenous dexmedetomidine is commonly used perioperatively, but an extravascular route of administration would be favoured in palliative care. Subcutaneous infusions provide desired therapeutic plasma concentrations with fewer unwanted effects as compared with intravenous dosing. We aimed to develop semi-mechanistic population models for predicting pharmacokinetic and pharmacodynamic profiles of dexmedetomidine after intravenous and subcutaneous dosing. METHODS: Non-linear mixed-effects modelling was performed using previously collected concentration and haemodynamic effects data from ten (eight in the intravenous phase) healthy human subjects, aged 19–27 years, receiving 1 µg/kg of intravenous or subcutaneous dexmedetomidine during a 10-min infusion. RESULTS: The absorption of dexmedetomidine from the subcutaneous injection site, and distribution to local subcutaneous fat tissue was modelled using a semi-physiological approach consisting of a depot and fat compartment, while a two-compartment mammillary model explained further disposition. Dexmedetomidine-induced reductions in plasma norepinephrine concentrations were accurately described by an indirect response model. For blood pressure models, the net effect was specified as hyper- and hypotensive effects of dexmedetomidine due to vasoconstriction on peripheral arteries and sympatholysis mediated via the central nervous system, respectively. A heart rate model combined the dexmedetomidine-induced sympatholytic effect, and input from the central nervous system, predicted from arterial blood pressure levels. Internal evaluation confirmed the predictive performance of the final models, as well as the accuracy of the parameter estimates with narrow confidence intervals. CONCLUSIONS: Our final model precisely describes dexmedetomidine pharmacokinetics and accurately predicts dexmedetomidine-induced sympatholysis and other pharmacodynamic effects. After subcutaneous dosing, dexmedetomidine is taken up into subcutaneous fat tissue, but our simulations indicate that accumulation of dexmedetomidine in this compartment is insignificant. CLINICALTRIALS.ORG: NCT02724098 and EudraCT 2015-004698-34 ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40262-020-00900-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-76580922020-11-13 Population Modelling of Dexmedetomidine Pharmacokinetics and Haemodynamic Effects After Intravenous and Subcutaneous Administration Ashraf, Muhammad W. Uusalo, Panu Scheinin, Mika Saari, Teijo I. Clin Pharmacokinet Original Research Article BACKGROUND AND OBJECTIVE: Dexmedetomidine is a potent agonist of α(2)-adrenoceptors causing dose-dependent sedation in humans. Intravenous dexmedetomidine is commonly used perioperatively, but an extravascular route of administration would be favoured in palliative care. Subcutaneous infusions provide desired therapeutic plasma concentrations with fewer unwanted effects as compared with intravenous dosing. We aimed to develop semi-mechanistic population models for predicting pharmacokinetic and pharmacodynamic profiles of dexmedetomidine after intravenous and subcutaneous dosing. METHODS: Non-linear mixed-effects modelling was performed using previously collected concentration and haemodynamic effects data from ten (eight in the intravenous phase) healthy human subjects, aged 19–27 years, receiving 1 µg/kg of intravenous or subcutaneous dexmedetomidine during a 10-min infusion. RESULTS: The absorption of dexmedetomidine from the subcutaneous injection site, and distribution to local subcutaneous fat tissue was modelled using a semi-physiological approach consisting of a depot and fat compartment, while a two-compartment mammillary model explained further disposition. Dexmedetomidine-induced reductions in plasma norepinephrine concentrations were accurately described by an indirect response model. For blood pressure models, the net effect was specified as hyper- and hypotensive effects of dexmedetomidine due to vasoconstriction on peripheral arteries and sympatholysis mediated via the central nervous system, respectively. A heart rate model combined the dexmedetomidine-induced sympatholytic effect, and input from the central nervous system, predicted from arterial blood pressure levels. Internal evaluation confirmed the predictive performance of the final models, as well as the accuracy of the parameter estimates with narrow confidence intervals. CONCLUSIONS: Our final model precisely describes dexmedetomidine pharmacokinetics and accurately predicts dexmedetomidine-induced sympatholysis and other pharmacodynamic effects. After subcutaneous dosing, dexmedetomidine is taken up into subcutaneous fat tissue, but our simulations indicate that accumulation of dexmedetomidine in this compartment is insignificant. CLINICALTRIALS.ORG: NCT02724098 and EudraCT 2015-004698-34 ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s40262-020-00900-3) contains supplementary material, which is available to authorized users. Springer International Publishing 2020-05-27 2020 /pmc/articles/PMC7658092/ /pubmed/32462542 http://dx.doi.org/10.1007/s40262-020-00900-3 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License, which permits any non-commercial use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Original Research Article
Ashraf, Muhammad W.
Uusalo, Panu
Scheinin, Mika
Saari, Teijo I.
Population Modelling of Dexmedetomidine Pharmacokinetics and Haemodynamic Effects After Intravenous and Subcutaneous Administration
title Population Modelling of Dexmedetomidine Pharmacokinetics and Haemodynamic Effects After Intravenous and Subcutaneous Administration
title_full Population Modelling of Dexmedetomidine Pharmacokinetics and Haemodynamic Effects After Intravenous and Subcutaneous Administration
title_fullStr Population Modelling of Dexmedetomidine Pharmacokinetics and Haemodynamic Effects After Intravenous and Subcutaneous Administration
title_full_unstemmed Population Modelling of Dexmedetomidine Pharmacokinetics and Haemodynamic Effects After Intravenous and Subcutaneous Administration
title_short Population Modelling of Dexmedetomidine Pharmacokinetics and Haemodynamic Effects After Intravenous and Subcutaneous Administration
title_sort population modelling of dexmedetomidine pharmacokinetics and haemodynamic effects after intravenous and subcutaneous administration
topic Original Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7658092/
https://www.ncbi.nlm.nih.gov/pubmed/32462542
http://dx.doi.org/10.1007/s40262-020-00900-3
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