Pharmacokinetics and pharmacodynamics of intranasal remimazolam—a randomized controlled clinical trial

Abstract

Purpose Remimazolam is a novel and ultra-short-acting sedative currently developed for intravenous use in procedural sedation, general anesthesia, and ICU sedation. However, intravenous administration is not always appropriate, depending on the patient or setting. This study evaluated intranasal administration as a potential alternative route. Methods The study used a randomized, double-blind, 9 period cross-over design to compare the pharmacokinetics, pharmacodynamics, and safety of single intranasal doses of 10, 20, and 40 mg remimazolam (as powder or solution) with intranasal placebo and 4 mg intravenous remimazolam. Results Intranasal remimazolam powder had a consistent absolute bioavailability of approximately 50%; Tmax was 10 min; AUC and Cmax were dose-proportional. The higher doses of intranasal solution, however, resulted in decreasing bioavailability and loss of dose-proportionality in AUC and Cmax despite complete drug absorption due to partial swallowing of dose and the resulting first-pass effect. Pharmacodynamics were generally consistent with PK. Peak effects (drowsiness, relaxation, any, memory, response time) were in similar ranges after intranasal (10 to 40 mg) as intravenous (4 mg) dosing and were partially, but not consistently, dose-related. Safety results were generally consistent with other benzodiazepines; however, intranasal remimazolam (but not placebo) caused nasal discomfort/pain, in some cases even severe. Conclusions Intranasal administration of remimazolam was safe and caused sedative effects. However, the severe pain and discomfort caused by intranasal remimazolam prohibit its use by this route of administration, at least with the currently available intravenous formulation.

Emerging Approaches in Intravenous Moderate and Deep Sedation

“…At higher intranasal (IN) doses, the bioavailability decreased, likely from incomplete delivery and resultant oral administration. Although bioavailability was approximately 50%, clinical effects were consistent and timely with a Tmax of 10 min; the clinical applicability of this intranasal formulation is non-existent, given the extreme pain on administration [ 19 ]. New formulations will be necessary in order to reduce the pain on administration for IN to be an offered route.…”

“…Small case reports have described the successful use of remimazolam and remifentanil for spine surgery with intraoperative motor-evoked potentials [ 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 ]. It has demonstrated success in a prospective, double-blind, multicenter (30 sites in United States), parallel group trial comparing it to midazolam and placebo for bronchoscopy in adults.…”

“…Time to extubation was determined by infusion rate and depth of sedation, unaffected by BMI, age, and ASA class. The clinical significance of these factors, albeit statistically significant, in reality are clinically of minimal significance as providers will likely decrease dosing in the obese and titrate down dosing in anticipation of extubation [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 ].…”

“…Remimazolam achieved greater in procedural success than midazolam, 87.1% versus 13.3% respectively. There was no difference in adverse events [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ].…”

“…Pharmacokinetically speaking, both remimazolam and oliceridine are appropriate for TCI. The context-sensitive decrement times (i.e., the times for a defined decrease in plasma and effect site concentrations such as by 25%, 50%, and 75% after continuous target controlled infusion of variable length) are calculated for remimazolam [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 ]. After an infusion of 4 h, the plasma context-sensitive halftime of remimazolam was 6.8 ± 2.4 min, while for the effect site concentration, it was 12 ± 2 min.…”