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Br J Anaesth. 2018 May;120(5):960-968. doi: 10.1016/j.bja.2017.11.100. Epub 2018 Feb 2.

Pharmacokinetic and pharmacodynamic study of intranasal and intravenous dexmedetomidine.

Author information

1
Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong.
2
Department of Anaesthesiology, University of Hong Kong, Hong Kong.
3
UCL School of Pharmacy, University College London, London, UK.
4
Great Ormond Street Institute of Child Health, University College London, London, UK. Electronic address: j.standing@ucl.ac.uk.
5
Department of Pharmacology and Pharmacy, University of Hong Kong, Hong Kong; Faculty of Pharmacy, The University of Sydney, New South Wales, Australia. Electronic address: philip.kwok@sydney.edu.au.
6
Department of Anaesthesiology, Queen Mary Hospital, Hong Kong.

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 atomisation (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 atomiser 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 atomiser (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 atomisation 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 atomisation or nasal drops. A similar degree of sedation can be achieved by either method.

CLINICAL TRIAL REGISTRATION:

HKUCTR-1617.

KEYWORDS:

NONMEM; administration; dexmedetomidine; intranasal; α2-agonists

PMID:
29661413
DOI:
10.1016/j.bja.2017.11.100
[Indexed for MEDLINE]
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