Time-to-Event Modeling for Remimazolam for the Indication of Induction and Maintenance of General Anesthesia

Abstract

Remimazolam is an ultra-short-acting benzodiazepine being investigated for induction and maintenance of general anesthesia and for procedural sedation. This dose-response analysis of 4 phase 2-3 studies evaluated covariates that may impact the pharmacodynamic profile (based on theoretical pharmacokinetic principles) and require dose adjustments in subpopulations, particularly elderly, and if remimazolam has cumulative properties. Covariates affecting the time to loss of consciousness and time to extubation were evaluated using Cox proportional hazards models. Factors affecting steady-state infusion rate required to produce adequate sedation were evaluated using linear regression. Variability in time to loss of consciousness was explained by induction dose, age, body mass index, and time from initiation of opioids to initiation of remimazolam. The steady-state infusion rate producing adequate sedation was higher in European than Japanese subjects due to differences in study design. American Society of Anesthesiologists physical status class 3 subjects had a 28% lower maintenance infusion rate than class 1 subjects. Other statistically significant covariates (American Society of Anesthesiologists class 2, estimated glomerular filtration rate, and sex) resulted in small (≤14%), non-clinically relevant differences. Factors affecting time to extubation included the last infusion rate (ie, tapering), the bispectral index score at the end of infusion, and sex. The time to extubation after remimazolam did not increase with increased cumulative dose of remimazolam or duration of surgery. This evaluation of remimazolam's pharmacodynamic profile, in the absence of pharmacokinetic data, informed dosing recommendations and showed that remimazolam does not have cumulative properties in the general anesthesia setting.

Keywords: anesthesia; dose-response; remimazolam; sedation; time-to-event analysis.

Figure 1

Kaplan‐Meier plot of the observed probability of not losing consciousness from the beginning of remimazolam infusion (seconds) by age group. The blue line is elderly (≥65 y), and the red line is nonelderly (<65 y). The boxes represent 95% confidence intervals.

Figure 2

Predicted probability of not losing consciousness over time (seconds) for remimazolam by (A) dose and age, (B) time between administration of opioids and remimazolam in seconds, and (C) body mass index (BMI) category. (A) The leftmost line represents induction dose = 12 mg/kg/h and age = 59 y (purple); the next line represents induction dose = 6 mg/kg/h and age = 75 y (brown); the next line represents induction dose = 6 mg/kg/h and age = 65 y (dark green); the next line represents induction dose = 6 mg/kg/h and age = 59 y (pea green); the next line represents induction dose = 6 mg/kg/h and age = 45 y (red); and the rightmost line represents induction dose = 6 mg/kg/h and age = 30 y (blue). (B) Induction dose is kept at 6 mg/kg/h and age = 50 y. The leftmost line represents a time between opioid and remimazolam administration of 600 sec (10 min, brown); the next line represents a time of 480 sec (8 min, green); the next line represents a time of 240 sec (4 min, red); and the rightmost line represents a time of 120 sec (2 min, blue). (C) Induction dose is kept at 6 mg/kg/h, and time between opioid and remimazolam is kept at 120 sec. The leftmost line represents obese subjects (green; BMI ≥30 kg/m²); the next line represents overweight subjects (red; BMI ≥25 to <30 kg/m²); and the rightmost line represents normal weight subjects (blue; BMI <25 kg/m²).

Figure 3

Kaplan‐Meier plot of the observed probability of not being extubated over time from end of remimazolam infusion (min) by age group. The blue line is elderly (≥65 y), and the red line is nonelderly (<65 y). The boxes represent 95% confidence intervals.

Figure 4

Predicted probability of not being extubated over time from end of remimazolam infusion (min) by (A) last remimazolam infusion rate (mg/kg/h) and bispectral index (BIS) score at the end of infusion for men, (B) last remimazolam infusion rate and BIS score at the end of infusion for women, and (C) last remimazolam infusion rate and sex at BIS score of 60 at the end of infusion. (A) Effect of infusion rate and BIS score in men, where the leftmost line represents men with infusion rate = 0.5 mg/kg/h and BIS = 60 (blue); then men with infusion rate = 0.5 mg/kg/h and BIS = 40 (brown); then men with infusion rate = 1 mg/kg/h and BIS = 60 (red); then males with infusion rate = 1 and BIS = 40 (pink); then men with infusion rate = 1.5 mg/kg/h and BIS = 60 (green); and men with infusion rate = 1.5 mg/kg/h and BIS = 40 (pea green). (B) Effect of infusion rate and BIS score in women, where the leftmost line represents women with infusion rate = 0.5 mg/kg/h and BIS = 60 (blue); then women with infusion rate = 0.5 mg/kg/h and BIS = 40 (brown); then women with infusion rate = 1 mg/kg/h and BIS = 60 (red); then women with infusion rate = 1 and BIS = 40 (pink); then women with infusion rate = 1.5 mg/kg/h and BIS = 60 (green); and women with infusion rate = 1.5 mg/kg/h and BIS = 40 (pea green). (C) Effect of sex and infusion rate when BIS score is constant, where (from left to right) the leftmost line represents women with infusion rate = 0.5 mg/kg/h and BIS = 60 (brown); the next line represents overlapping lines for both men with infusion rate = 0.5 mg/kg/h and BIS = 60 (blue) and women with infusion rate = 1 mg/kg/h and BIS = 60 (pink); the next line represents overlapping lines for men with infusion rate = 1 mg/kg/h and BIS = 60 (red) and women with infusion rate = 1.5 mg/kg/h and BIS = 60 (pea green); and the rightmost line represents men with infusion rate = 1.5 mg/kg/h and BIS = 60 (green).