Pharmacokinetics

Crossover study

Anesthesia

Bioavailability

Placebo

Onset of action

NONMEM

Alternative medicine

Sedation

Pharmacodynamics

Pharmacology

Nasal administration

Dexmedetomidine

Medicine

Pathology

British Journal of Anaesthesia

BackgroundIntranasal 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).MethodsThis 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.ResultsThe 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.ConclusionsThere is no difference in bioavailability with atomisation or nasal drops. A similar degree of sedation can be achieved by either method.Clinical trial registrationHKUCTR-1617.

Pharmacokinetic and pharmacodynamic study of intranasal and intravenous dexmedetomidine