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. b-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 (ts.d.) peak plasma concentration of midazolam of 71 (t25 ng ml x1 ) was reached after 14 (t5 min). Mean bioavailability following intranasal administration was 0.83t0.19. After intravenous and intranasal administration, the pharmacokinetic estimates of midazolam were: mean volume of distribution at steady state 1.11t0.25 l kg x1 , mean systemic clearance 16.1t4.1 ml min x1 kg x1 and harmonic mean initial and terminal half lives 8.4t2.4and 79t30 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.

Naloxone without the needle − systematic review of candidate routes for non-injectable naloxone for opioid overdose reversal

“…However, the buccal route has been successfully used to develop non-injectable versions of other medications previously available as injection only. Buccal midazolam ('Buccolam') produces rapid onset of action and its bioavailability (80%) is slightly superior to nasal midazolam (73-75%; Dale et al, 2006;Knoester et al, 2002;Schwagmeier et al, 1998;Taylor et al, 2008). Buccolam is now a licensed treatment that parents can administer while awaiting professional medical care (MHRA, 2011).…”

The use of intranasal midazolam in the treatment of paediatric dental patients*

“…Transmucosal routes of drug administration have been used as premedicants in this age group [6,7]. Intranasal midazolam has been found to be effective in doses ranging from 0.2 to 0.6 mg.kg )1 when used for conscious sedation and as a premedicant [8][9][10]. This technique has advantages when compared with oral administration as the bioavailability of intranasally administered midazolam is approximately 55%, compared with 15% when administered orally [11,12].…”

Intranasal Delivery of Antiepileptic Medications for Treatment of Seizures

“…[25][26][27][28][29][30][31][32][33][34] The main considerations from these data might be whether maximum plasma concentrations represented by C max are within ranges known to produce pharmacologic effects, and the second consideration is whether the concentrations are achieved rapidly enough to be appropriate for treating a seizure. Well-designed nasal preparations may demonstrate a pharmacokinetic profile in which the rate and extent of drug exposure is superior to intramuscular injection and approximates IV infusion (FIG.…”