Pharmacokinetics and pharmacodynamics of a new highly concentrated intranasal midazolam formulation for conscious sedation.

Abstract

To evaluate the pharmacokinetics, pharmacodynamics, nasal tolerance and effects on sedation of a highly concentrated aqueous intranasal midazolam formulation (Nazolam) and to compare these to intravenous midazolam. In this four-way crossover, double-blind, double-dummy, randomized, placebo-controlled study, 16 subjects received 2.5mg Nazolam, 5.0mg Nazolam, 2.5mg intravenous midazolam or placebo on different occasions. Pharmacokinetics of midazolam and α-hydroxy-midazolam were characterized and related to outcome variables for sedation (saccadic peak velocity, the Bond and Lader visual analogue scale for sedation, the simple reaction time task and the observer's assessment of alertness/sedation). Nasal tolerance was evaluated through subject reporting, and ear, nose and throat examination. Nazolam bioavailability was 75%. Maximal plasma concentrations of 31ngml-1 (CV, 42.3%) were reached after 11min (2.5mg Nazolam), and of 66ngml-1 (coefficient of variability, 31.5%) after 14min (5.0mg Nazolam). Nazolam displayed a significant effect on OAA/S scores. Sedation onset (based on SPV change) occurred 1±0.7min after administration of 2.5mg intravenous midazolam, 7±4.4min after 2.5mg Nazolam, and 4±1.8min after 5mg Nazolam. Sedation duration was 118±95.6min for 2.5mg intravenous midazolam, 76±80.4min for 2.5mg Nazolam, and 145±104.9min for 5.0mg Nazolam. Nazolam did not lead to nasal mucosa damage. This study demonstrates the nasal tolerance, safety and efficacy of Nazolam. When considering the preparation time needed for obtaining venous access, conscious sedation can be achieved in the same time span as needed for intravenous midazolam. Nazolam may offer important advantages in conscious sedation.