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Pharmacokinetic and pharmacodynamic study of intranasal and intravenous dexmedetomidine

Li, A; Yuen, VM; Goulay-Dufay, S; Sheng, Y; Standing, JF; Kwok, PCL; Leung, MKM; ... Irwin, MG; + view all (2018) Pharmacokinetic and pharmacodynamic study of intranasal and intravenous dexmedetomidine. British Journal of Anaesthesia , 120 (5) pp. 960-968. 10.1016/j.bja.2017.11.100. Green open access

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Abstract

Background: Intranasal dexmedetomidine produces safe, effective sedation in children and adults. It may be administered by drops from a syringe or by nasal mucosal atomization (MAD NasalTM). / Methods: This prospective, three-period, crossover, double-blind study compared the pharmacokinetic (PK) and pharmacodynamic (PD) profile of i.v. administration with these two different modes of administration. In each session each subject received 1 μg kg−1 dexmedetomidine, either i.v., intranasal with the atomizer or intranasal by drops. Dexmedetomidine plasma concentration and Ramsay sedation score were used for PK/PD modelling by NONMEM. / Results: The i.v. route had a significantly faster onset (15 min, 95% CI 15–20 min) compared to intranasal routes by atomizer (47.5 min, 95% CI 25–135 min), and by drops (60 min, 95%CI 30–75 min), (P<0.001). There was no significant difference in sedation duration across the three treatment groups (P=0.88) nor in the median onset time between the two modes of intranasal administration (P=0.94). A 2-compartment disposition model, with transit intranasal absorption and clearance driven by cardiac output using the well-stirred liver model, was the final PK model. Intranasal bioavailability was estimated to be 40.6% (95% CI 34.7–54.4%) and 40.7% (95% CI 36.5–53.2%) for atomization and drops respectively. Sedation score was modelled via a sigmoidal Emax model driven by an effect compartment. The effect compartment had an equilibration half time 3.3 (95% CI 1.8–4.7) min−1, and the EC50 was estimated to be 903 (95% CI 450–2344) pg ml−1. / Conclusions: There is no difference in bioavailability with atomization or nasal drops. A similar degree of sedation can be achieved by either method. / Clinical trial registration: HKUCTR-1617.

Type: Article
Title: Pharmacokinetic and pharmacodynamic study of intranasal and intravenous dexmedetomidine
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.bja.2017.11.100
Publisher version: https://doi.org/10.1016/j.bja.2017.11.100
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. // A corrigendum to this article has been published at: https://doi.org/10.1016/j.bja.2018.07.001.
Keywords: α2-agonists; dexmedetomidine; administration; intranasal; NONMEM
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > UCL School of Pharmacy > Practice and Policy
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > UCL GOS Institute of Child Health > Infection, Immunity and Inflammation Dept
URI: https://discovery.ucl.ac.uk/id/eprint/10037778
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