Population Modelling of Dexmedetomidine Pharmacokinetics and Haemodynamic Effects After Intravenous and Subcutaneous Adm
- PDF / 2,146,680 Bytes
- 16 Pages / 595.276 x 790.866 pts Page_size
- 23 Downloads / 208 Views
ORIGINAL RESEARCH ARTICLE
Population Modelling of Dexmedetomidine Pharmacokinetics and Haemodynamic Effects After Intravenous and Subcutaneous Administration Muhammad W. Ashraf1 · Panu Uusalo1,2 · Mika Scheinin3,4 · Teijo I. Saari1,2
© The Author(s) 2020
Abstract Background and Objective Dexmedetomidine is a potent agonist of α2-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 (https://doi.org/10.1007/s40262-020-00900-3) contains supplementary material, which is available to authorized users. * Teijo I. Saari [email protected] 1
Department of Anaesthesiology and Intensive Care, University of Turku, Kiinamyllynkatu 4‑8 (11A5), P.O. Box 52, 20521 Turku, Finland
2
Division of Perioperative Services, Intensive Care and Pain Medicine, Turku University Hospital, Turku, Finland
3
Institute
Data Loading...
