Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers

Abstract

Aims: To investigate the pharmacokinetic and pharmacodynamic profile of midazolam administered as a concentrated intranasal spray, compared with intravenous midazolam, in healthy adult subjects.

Methods: Subjects were administered single doses of 5 mg midazolam intranasally and intravenously in a cross-over design with washout period of 1 week. The total plasma concentrations of midazolam and the metabolite 1-hydroxymidazolam after both intranasal and intravenous administration were described with a single pharmacokinetic model. beta-band EEG activity was recorded and related to midazolam plasma concentrations using an exponential pharmacokinetic/pharmacodynamic model.

Results: Administration of the intranasal spray led to some degree of temporary irritation in all six subjects, who nevertheless found intranasal administration acceptable and not painful. The mean (+/-s.d.) peak plasma concentration of midazolam of 71 (+/-25 ng ml-1) was reached after 14 (+/-5 min). Mean bioavailability following intranasal administration was 0.83+/-0.19. After intravenous and intranasal administration, the pharmacokinetic estimates of midazolam were: mean volume of distribution at steady state 1.11+/-0.25 l kg-1, mean systemic clearance 16.1+/-4.1 ml min-1 kg-1 and harmonic mean initial and terminal half lives 8.4+/-2.4 and 79+/-30 min, respectively. Formation of the 1-hydroxymetabolite after intranasal administration did not exceed that after intravenous administration.

Conclusions: In this study in healthy volunteers a concentrated midazolam nasal spray was easily administered and well tolerated. No serious complications of the mode of administration or the drug itself were reported. Rapid uptake and high bioavailability were demonstrated. The potential of midazolam given via a nasal spray in the acute treatment of status epilepticus and other seizure disruptions should be evaluated.

Figures

Figure 1

Fit of the composite model to the concentration vs time data for midazolam and 1-hydroxymidazolam in one volunteer. Solid lines indicate the time course of midazolam concentrations (▪) and 1-hydroxymidazolam concentrations (♦) after intravenous administration. Dotted lines indicate the time course of midazolam concentrations (▴) and 1-hydroxymidazolam concentrations (▾) after intranasal administration.

Figure 2

Individual plasma concentration vs time curves for midazolam (solid lines) and 1-hydroxymidazolam (broken lines) after intranasal administration of 5 mg midazolam. The bold curves represent the mean pharmacokinetic model fit to the data.

Figure 3

Individual EEG effect vs predicted plasma midazolam concentration after i.v. (solid lines) and i.n. (broken lines) administration of the drug. The bold curve represents the mean pharmacodynamic model fit.