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

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%; T(max) was 10 min; AUC and C(max) were dose-proportional. The higher doses of intranasal solution, however, resulted in decreasing bioavailability and loss of dose-proportionality in AUC and C(max) 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.