Population pharmacokinetic analysis of remimazolam after continuous infusion for sedation in critically ill patients

Introduction: The aim of the present prospective study was to model the population pharmacokinetics of remimazolam after continuous infusion in critically ill patients, and to provide a guide for remimazolam administration based on simulations that were conducted. Patients and methods: A total of 32 critically ill patients were enrolled in this study, with 236 plasma concentration data ultimately included for modeling. Plasma concentrations of remimazolam were quantified by a validated high-performance liquid chromatography-tandem mass spectrometry method, and the data were analyzed using non-linear mixed effect modeling. Concentration-time curves of remimazolam at different induction and maintenance doses were simulated and context-sensitive decrement times (CSDTs) were calculated using Monte Carlo simulations. Results: A two-compartment model appropriately described the concentration-time profile of remimazolam in critically ill patients. The elimination clearance, volume of the central compartment, volume of the peripheral compartment, and peripheral compartmental clearance were estimated to be 58.2 L/h (95% CI, 47.8-72.3 L/h), 25.5 L (95% CI, 16.8-33.3 L), 34.5 L (95% CI, 26.0-58.8 L) and 21.9 L/h (95% CI, 12.2-34.6 L/h), respectively. No covariates significantly influenced the pharmacokinetic parameters of remimazolam. Internal validation proved the reliable predictive performance of the model. The CSDTs of remimazolam (10%-90%) was independent of the infusion time. Conclusion: Remimazolam showed a predictable pharmacokinetic profile and was demonstrated to be suitable for long-term sedation in the intensive care unit, with dose adjustments only required dependent on the degree of the sedative effect.