<p>Metabolism of remimazolam in primary human hepatocytes during continuous long-term infusion in a 3-D bioreactor system</p>

Abstract

Background Remimazolam is an ultra-short acting benzodiazepine under development for procedural sedation and general anesthesia. It is hydrolyzed by CES1 to an inactive metabolite (CNS7054). Purpose In this study, the effect of continuous remimazolam exposure on its metabolism and on CES1 expression was investigated in a dynamic 3-D bioreactor culture model inoculated with primary human hepatocytes. Methods Remimazolam was continuously infused into bioreactors for 5 days at a final concentration of 3,000 ng/ml (6.8 µM). In parallel, 2-D cultures were run with cells from the same donors, but with discontinuous exposure to remimazolam. Results Daily measurement of clinical chemistry parameters (glucose, lactate, urea, ammonia, and liver enzymes) in culture supernatants indicated no noxious effect of remimazolam on hepatocyte integrity as compared to untreated controls. Concentrations of remimazolam reached steady-state values of around 250 ng/ml within 8 hours in 3-D bioreactors whereas in 2-D cultures remimazolam concentrations declined to almost zero within the same time frame. Levels of CNS7054 showed an inverse time-course reaching average values of 1,350 ng/ml in perfused 3-D bioreactors resp. 2,800 ng/ml in static 2-D cultures. Analysis of mRNA expression levels of CES1 indicated no changes in gene expression over the culture period. Conclusion The results indicated a stable metabolism of remimazolam during 5 days of continuous exposure to clinically relevant concentrations of the drug. Moreover, there was no evidence for a harmful effect of remimazolam exposure on the integrity and metabolic activity of in vitro cultivated primary human hepatocytes.

Sedation outcomes for remimazolam, a new benzodiazepine

“…J Jpn Soc Clin Anesth 37, S202, 2017], which suggests that prolonged exposure under traumatic conditions could promote metabolic changes. However, a recent study reported that remimazolam metabolism was stable during continuous long-term infusion (5 days) and that remimazolam exposure had no harmful effects on the integrity and metabolic activity of hepatocytes [27].…”

Current status of perioperative hypnotics, role of benzodiazepines, and the case for remimazolam: a narrative review

“…132 A bioreactor study using human hepatocytes showed no adverse changes in remimazolam metabolism over a 5 day period. 133 However, there remains a need for it to be assessed in proper randomised clinical trials against current standard drugs (propofol, midazolam, and dexmedetomidine).…”

A population pharmacodynamic Markov mixed‐effects model for determining remimazolam‐induced sedation when co‐administered with fentanyl in procedural sedation

“…Remimazolam is an ultra-short acting benzodiazepine administered by IV injection or infusion, which is approved for induction and maintenance of general anesthesia in Japan (Anerem ® ) and procedural sedation in the US (ByFavo™) and China (Ruima®). Remimazolam is rapidly hydrolyzed by liver carboxylesterase to an inactive metabolite (CNS7054) 1 and is, therefore, superior to midazolam with its rapid and predictable onset and offset 2 . Remimazolam may be used with fentanyl to minimize discomfort level during uncomfortable medical procedures (e.g., colonoscopy or bronchoscopy).…”