PHARMACOKINETICS AND PHARMACODYNAMICS OF MIDAZOLAM AFTER INTRANASAL ADMINISTRATION

This study aimed to characterize the pharmacokinetics and pharmacodyna mics of midazolam after intranasal administration to healthy volunteer s. Eight participants were given 0.25 mg/kg intranasally and 2 mg intr avenously in a randomized, crossover fashion. Blood samples for determ ination of plasma concentrations of midazolam and measures of cognitiv e function (using the digit symbol substitution test) were obtained at baseline and 5, 10, 20, 30, 45, 60, 90, 120, 180, 240, and 360 minute s after administration of study medications. Plasma samples were analy zed by gas chromatography (% coefficient of variation < 10%). Pharmaco kinetic data were fitted using iterative two-stage analysis to a two-c ompartment model. Pharmacodynamic data were fitted by a baseline subtr action Hill-type model. The mean (SD) for total clearance, distributio nal clearance, volume of distribution in the central compartment, volu me of distribution in the peripheral compartment, absorption rate cons tant, bioavailability, and half-life were 0.57 (0.26) L/hr/kg 0.31 (0. 29) L/hr/kg 0.27 (0.14) L/kg, 0.67 (0.11) L/kg, 2.46 (1.72) hr(-1), 50 % (13%), and 3.1 (0.84) hours, respectively The mean (SD) for the conc entration at which She effect is half maximal (EC50) and the maximal e ffect or the maximal change in effect measure from baseline (E-max) we re 63.1 (21.2) ng/mL and 52.8 (21.1) correct substitutions, respective ly. After intranasal administration, midazolam concentrations rapidly achieve values considered sufficient to induce conscious sedation and produce predictable changes in digit symbol substitution score.