Remimazolam: Non-Clinical and Clinical Profile of a New Sedative/Anesthetic Agent

Abstract

A program to identify novel intravenous sedatives with a short and predictable duration of action was initiated in the late 1990’s by Glaxo Wellcome. The program focussed on the identification of ester-based benzodiazepine derivatives that are rapidly broken down by esterases. Remimazolam was identified as one of the lead compounds. The project at Glaxo was shelved for strategic reasons at the late lead optimization stage. Via the GSK ventures initiative, the program was acquired by the small biotechnology company, TheraSci, and, through successive acquisitions, developed as the besylate salt at CeNeS and PAION. The development of remimazolam besylate has been slow by industry standards, primarily because of the resource limitations of these small companies. It has, however, recently been approved for anesthesia in Japan and South Korea, procedural sedation in the United States, China, and Europe, and for compassionate use in intensive care unit sedation in Belgium. A second development program of remimazolam was later initiated in China, using a slightly different salt form, remimazolam tosylate. This salt form of the compound has also recently been approved for procedural sedation in China. Remimazolam has the pharmacological profile of a classical benzodiazepine, such as midazolam, but is differentiated from other intravenous benzodiazepines by its rapid conversion to an inactive metabolite resulting in a short onset/offset profile. It is differentiated from other intravenous hypnotic agents, such as propofol, by its low liability for cardiovascular depression, respiratory depression, and injection pain. The benzodiazepine antagonist flumazenil can reverse the effects of remimazolam in case of adverse events and further shorten recovery times. The aim of this review is to provide an analysis of, and perspective on, published non-clinical and clinical information on 1) the pharmacology, metabolism, pharmacokinetics, and pharmacodynamic profile of remimazolam, 2) the profile of remimazolam compared with established agents, 3) gaps in the current understanding of remimazolam, 4) the compound’s discovery and development process and 5) likely future developments in the clinical use of remimazolam.

Remimazolam: pharmacological characteristics and clinical applications in anesthesiology

“…After 24 h of remimazolam injection (0.2 or 0.3 mg/kg IV), more than 80% of the dose was detected in urine as a metabolite and less than 1% of the original dose was detected as unchanged drug [ 14 ]. The plasma protein binding of remimazolam was approximately 92%, predominantly serum albumin [ 1 ].…”

“…Because ICU patients are critically ill with essential organ failure (hepatic or renal), the ideal drug of choice in such a scenario would be a short-acting agent with metabolism independent of the liver or kidney. In this respect, remimazolam could theoretically be a promising drug for long-term sedation in ICU patients due to its favorable properties of organ-independent metabolism, minimal accumulation, and availability of a reversal drug [ 1 ].…”

“…The hypnotic effect of remimazolam can be reversed using flumazenil, which is an antagonist of the positive allosteric modulator effects of BDZs. However, reversal is not possible for several other hypnotics, including propofol [ 1 ]. Reversal of the sedative effect of remimazolam by flumazenil has been well described in several previous studies [ 6 , 41 ].…”

“…Remimazolam besylate (Byfavo injection in South Korea, Anerem ® in Japan, Aptimyda TM in EU, ByFavo TM in the USA, and Ruima ® in China) is a water-soluble, ultra-short-acting intravenous (IV) benzodiazepine (BDZ). It has recently been approved as a general anesthetic (in January 2020 in Japan and January 2021 in South Korea) and for use in procedural sedation (in July 2020 in the USA and China, March 2021 in Europe, and August 2021 in South Korea) in adults [1].…”

“…Similar to other BDZs, flumazenil can be used to reverse the sedation effect of remimazolam [ 6 ]. Owing to its favorable properties, including rapid onset, organ-independent metabolism, short duration of action, predictable recovery, availability of a reversal agent, and a superior safety profile similar to other BDZs in terms of hemodynamic stability, remimazolam appears to have several advantages over currently available short-acting sedative drugs [ 1 , 7 ].…”