title: Intranasal midazolam: pharmacokinetics and pharmacodynamics assessed by quantitative EEG in healthy volunteers.
abstract: The pharmacokinetics and pharmacodynamics of a highly concentrated cyclodextrin-based intranasal (i.n.) midazolam formulation containing the absorption-enhancer chitosan were studied in 12 healthy volunteers and compared with intravenous (i.v.) midazolam. The pharmacodynamic (PD) effects were assessed using quantitative electroencephalography (EEG). Maximal plasma concentrations of 63 and 110 ng/ml were reached at 8.4 and 7.6 min after 3 and 6 mg i.n. midazolam, respectively. After 5 mg i.v. and 6 and 3 mg i.n. midazolam, the times to onset of significant EEG effects in the β2 band (18-25 Hz) were 1.2, 5.5, and 6.9 min, respectively, and the times to loss of response to auditory stimuli were 3.0, 8.0, and 15.0 min, respectively. A sigmoid maximum-effect (E(max)) model indicated disequilibrium between plasma and effect-site concentrations, with equilibration half-lives of 2.1-4.8 min. The observed pharmacokinetic-PD (PK-PD) properties suggest that i.n. midazolam deserves to be evaluated as an easy and noninvasive method of administering a first benzodiazepine dose, e.g., in out-of-hospital emergency settings with no immediate i.v. access.
authors.affiliation: Department of Neurology, Division of Clinical Neurophysiology, University Hospital Basel, Basel, Switzerland.
authors.forename: M
authors.initials: M
authors.lastname: Hardmeier
authors.forename: R
authors.initials: R
authors.lastname: Zimmermann
authors.forename: S
authors.initials: S
authors.lastname: Rüegg
authors.forename: M
authors.initials: M
authors.lastname: Pflüger
authors.forename: S
authors.initials: S
authors.lastname: Deuster
authors.forename: K
authors.initials: K
authors.lastname: Suter
authors.forename: M
authors.initials: M
authors.lastname: Donzelli
authors.forename: J
authors.initials: J
authors.lastname: Drewe
authors.forename: S
authors.initials: S
authors.lastname: Krähenbühl
authors.forename: P
authors.initials: P
authors.lastname: Fuhr
authors.forename: M
authors.initials: M
authors.lastname: Haschke
mesh_terms: D000281:Administration, Intranasal; D000328:Adult; D018592:Cross-Over Studies; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects*; D006801:Humans; D008297:Male; D008874:Midazolam / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000494:pharmacology*; D008875:Middle Aged; D008954:Models, Biological
chemical_list: D008874:Midazolam