Pharmacokinetic and pharmacodynamic study of intranasal and intravenous dexmedetomidine

• Published in: British journal of anaesthesia : BJA Vol. 120; no. 5; pp. 960 - 968
• Main Authors: Li, A., Yuen, V.M., Goulay-Dufaÿ, S., Sheng, Y., Standing, J.F., Kwok, P.C.L., Leung, M.K.M., Leung, A.S., Wong, I.C.K., Irwin, M.G.
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.05.2018
• Subjects: administration; dexmedetomidine; intranasal; NONMEM; α2-agonists; dexmedetomidine; intranasal; administration; α2-agonists; NONMEM
• ISSN: 0007-0912; 1471-6771; 1471-6771
• DOI: 10.1016/j.bja.2017.11.100

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). 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. 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. There is no difference in bioavailability with atomisation or nasal drops. A similar degree of sedation can be achieved by either method. HKUCTR-1617.