Pharmacokinetic Properties and Therapeutic Effectiveness of Remimazolam in ICU Patients With Mechanical Ventilation: A Preliminary Study

Abstract

The pharmacokinetic (PK) profile of remimazolam, a ultra-short-acting benzodiazepine, has been investigated for procedural sedation and anesthesia, but its pharmacokinetics, pharmacodynamics, and optimal dosing for ICU sedation are still unclear. This prospective, single-center, double-blind randomized controlled trial studied ICU adults on mechanical ventilation for over 24 h. Participants were divided into three groups, each receiving a 0.2 mg/kg remimazolam loading dose in less than a minute, followed by maintenance doses of 0.1, 0.3, or 0.5 mg/kg/h. Plasma concentrations of remimazolam and its metabolites were measured using UPLC-MS/MS, and pharmacokinetic parameters were calculated using one-compartmental methods with WinNolin. The study also assessed pharmacodynamic indicators (RASS score) and the impact of the clinical indicators on pharmacokinetic parameters. The study on 36 ICU patents using a one-compartment model found that after 24 h of continuous intravenous remimazolam infusion, the drug had a median clearance rate of 22.23 mL/kg/min and a volume of distribution of 2656.58 mL/kg. The half-life was 101.791 min in ventilated patients, while its metabolites had a slower clearance rate of 0.49 mL/kg/min and an longer half-life of 656.02 min. Sedation levels were mild to moderate at dosed of 0.1-0.3 mg/kg/h. Liver function significantly affected remimazolam metabolism, influencing the half-life (R² = 0.36, p = 0.00013) and clearance (R² = 0.13, p = 0.04). The pharmacokinetic study indicates that remimazolam is effective and safe for ICU patients on mechanical ventilation, with a 24-h infusion demonstrating rapid clarence and a clear dose-effect relationship. It provides mild to moderate sedation at 0.1-0.3 mg/kg/h, but caution is advised for patients with severe liver dysfunction due to its impact on drug metabolism. Trial Registration: ClinicalTrials.gov identifier: NCT05480787.

Keywords: intensive care; mechanical ventilation; pharmacokinetics; remimazolam; sedation.

FIGURE 1

The goodness of fit plot for the one compartment model. (A) Semi‐logarithmic plot of concentration‐time profiles of remimazolam. (B) Predicted vs. observed concentration for remimazolam within 0.5–2 fold error range. C _obs observed values of concentration, C _pre predicted value of concentration.

FIGURE 2

The goodness of fit plot for the one compartment model. (A) Semi‐logarithmic plot of concentration‐time profiles of remimazloam metabolite. (B) Predicted vs. observed concentration for remimazolam within 0.5–2 fold error range. C _obs observed values of concentration, C _pre predicted value of concentration.

FIGURE 3

RASS scores of different groups.

FIGURE 4

Pearson correlation analysis of baseline data and half‐time.

FIGURE 5

Pearson correlation analysis of baseline data and clearance.