Pharmacokinetics and pharmacodynamics of intranasal remimazolam\u2014a randomized controlled clinical trial

Marija Pesic,Frank Schippers,Thomas Stoehr,Lyn Webster,Martin Donsbach,Rob Saunders

doi:10.1007/s00228-020-02984-z

Marija Pesic, Frank Schippers + Show 4 more

Open Access

https://doi.org/10.1007/s00228-020-02984-z

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Abstract

PurposeRemimazolam 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.MethodsThe 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.ResultsIntranasal 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.ConclusionsIntranasal 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.

Highlights

Remimazolam is a novel, ultra-short-acting benzodiazepine currently being developed for intravenous use for sedation during short medical procedures, the induction and maintenance of general anesthesia, and for ICU sedation [1]
The abundance of metabolizing esterases as well as the lack of pharmacological activity of the main metabolite makes the plasma clearance of the drug high and predictable, which translates to faster recovery of the patient after sedation compared with patients given, e.g., midazolam [2, 3]; safety data are comparable with those of midazolam and show significant advantages vs propofol [1]
PK endpoints, including C0 (IV only), Cmax, Tmax, AUC, and t1/2 were calculated using a non-compartmental model in Phoenix® WinNonlin and the evaluation included data from all subjects who received at least 1 dose of trial medication and had sufficient concentration-time data to permit calculation of at least 1 key parameter (Cmax, AUC0-last, or AUC0-inf)

Summary

Introduction

Remimazolam is a novel, ultra-short-acting benzodiazepine currently being developed for intravenous use for sedation during short medical procedures, the induction and maintenance of general anesthesia, and for ICU sedation [1]. Remimazolam is rapidly hydrolyzed to an inactive metabolite, CNS7054, by the activity of carboxylesterase-1, PAION Deutschland GmbH, Martinstr. In some situations and some patient populations, intravenous administration may be problematic. In an emergency/trauma setting, intravenous access is sometimes not available. In those situations, alternative routes of administration, such as oral or intranasal, can be indispensible [4, 5]. Oral bioavailability of remimazolam is very low, making it an unsuitable alternative route of

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