Abstract
BACKGROUND: The pharmacokinetics of prolonged remimazolam infusion in patients undergoing long-term mechanical ventilation remain unclear. This study aimed to evaluate the pharmacokinetics of remimazolam administered continuously for 24 h. METHODS: This open-label pharmacokinetic analysis enrolled patients requiring mechanical ventilation into two groups: the surgical group, which received remimazolam during and after surgery, and the medical ICU group, which received remimazolam in the intensive care unit (ICU). Remimazolam was administered at a fixed rate of 0.1 mg/kg/h for ≥ 24 h, and blood samples were collected at regular intervals. Plasma remimazolam concentrations were measured by tandem mass spectrometry. RESULTS: Twenty patients (10 in each group) completed the study. The median duration of remimazolam infusion was 24.0 h in the surgical group and 102.0 h in the medical ICU group. The steady-state plasma concentrations in both the surgical and medical ICU groups exhibited modest intrasubject variability (4.46-32.73%) and moderate intersubject variability (16.45-31.71%), with all values falling within clinically acceptable intermediate ranges. The plasma remimazolam concentration at the end of infusion was 130.7 ng/mL (95% confidence interval [CI] 115.2-146.1) in the surgical group and 134.3 ng/mL (95% CI 98.7-170.0) in the medical ICU group. Noncompartmental analysis showed that the clearance was 54.3 L/h (95% CI 47.6-61.8) and 55.6 L/h (95% CI 42.8-72.1) (P = 0.856), while the volume of distribution at steady state was 284 L (95% CI 215-376) and 316 L (95% CI 142-707) (P = 0.780), with no statistically significant differences between the groups. CONCLUSIONS: In this preliminary study, both the surgical ICU group (approximately 24 h) and the medical ICU group (beyond 24 h) showed no evidence of time-dependent accumulation of plasma remimazolam, indicating a generally stable pharmacokinetic profile under the examined conditions. TRIAL REGISTRATION: In compliance with the Japanese Clinical Trials Act, the study was classified as a Specified Clinical Trial owing to the use of unapproved pharmaceuticals, which were reviewed by a certified review board (CRB) and registered in the Japan Registry of Clinical Trials (jRCTs041200076) on December 15, 2020.