Journal
BRITISH JOURNAL OF ANAESTHESIA
Volume 120, Issue 5, Pages 960-968Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.bja.2017.11.100
Keywords
alpha 2-agonists; dexmedetomidine; administration; intranasal; NONMEM
Categories
Funding
- Department of Anaesthesiology
- Department of Pharmacology and Pharmacy, University of Hong Kong
- UK Medical Research Council Fellowship [M008665]
- MRC [MR/M008665/1] Funding Source: UKRI
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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 Nasal (TM)). 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 mu g 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 E-max 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.
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