Target-controlled Infusion of Remimazolam in Healthy Volunteers Shows Some Acute Tolerance

Abstract

Background Remimazolam exhibits sedative properties by binding to γ-aminobutyric acid type A receptors. Remimazolam is administered as bolus dose or continuous infusion, but has not been studied using target-controlled infusion (TCI). We quantified the relationship between the remimazolam concentration, modified observers assessment of alertness and sedation (MOAAS) score and bispectral index (BIS) using TCI. Methods We performed a three-period, cross-over, dose-ranging clinical trial in 24 healthy volunteers using age- and sex-stratification. Data collected in the first period, where remimazolam was administered alone using a step-up and step-down TCI protocol, were used for this analysis. Remimazolam concentrations, MOAAS scores and BIS values were collected at each step at steady state. Data were analyzed using non-linear mixed-effects modelling methodology. Results The relationship between remimazolam, BIS and MOAAS differed between step-up and step-down infusions at similar remimazolam target concentrations. Tolerance, driven by remimazolam or CNS7054, significantly improved overall model fit (p<0.01) for both BIS and MOAAS models. Following 30 minutes of repeated bolus dosing, mimicking the regimen in the label for procedural sedation, the BIS and probability of MOAAS 2/3 were predicted to be 54 (95% PI: 44,67) and 2% (0,32%) versus 58 (48,70) and 8% (0,36%) in a model without and with tolerance, respectively. Following 60 minutes of continuous infusion, mimicking the regimen in the label for general anaesthesia, the BIS and probability of MOAAS 0 were predicted to be 40 (33,50) and 87% (18,100%) versus 50 (41,60) and 59% (6,99%) in a model without and with tolerance, respectively. Conclusions In this study, we showed that remimazolam-induced sedation is prone to tolerance development, which is potentially mediated by the CNS7054 concentration. The clinical consequences are however limited in situations where remimazolam is titrated to effect.