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. 2025 Jul;135(1):206-217.
doi: 10.1016/j.bja.2025.02.038. Epub 2025 Apr 30.

Development and analysis of a remimazolam pharmacokinetics and pharmacodynamics model with proposed dosing and concentrations for anaesthesia and sedation

Douglas J Eleveld  1 , Pieter J Colin  2 , Johannes P Van den Berg  2 , Jeroen V Koomen  2 , Thomas Stoehr  3 , Michel M R F Struys  4
Affiliations

Development and analysis of a remimazolam pharmacokinetics and pharmacodynamics model with proposed dosing and concentrations for anaesthesia and sedation

Douglas J Eleveld et al. Br J Anaesth. 2025 Jul.

Abstract

Background: Pharmacokinetic-pharmacodynamic (PK-PD) models of remimazolam and their covariate relationships are useful for understanding drug disposition and predicting drug effects. Although clinical studies have shown that remimazolam induction doses decline with advancing age, this property is not reflected in existing models. The purpose of this investigation was to develop a PK-PD model for remimazolam and perform covariate analysis to maximise its utility across broad, diverse populations and to evaluate its consistency with clinical observations of drug dosing.

Methods: Arterial and venous concentrations of remimazolam and its metabolite, Modified Observer's Assessment of Alertness and Sedation score and bispectral index were determined in 20 studies. Final population models were developed with covariate analysis. Simulations of drug administration for sedation and anaesthesia for this and previously published models were compared with the results of clinical studies.

Results: Model development proceeded from 933 individuals aged 6-93 yr and weight 21-171 kg. PK data from studies with extracorporeal membrane oxygenation and treatment in ICU were considered in a post hoc analysis. Simulations of target-controlled infusion with the final model targeting sedation (Modified Observer's Assessment of Alertness and Sedation score 2 or 3) or anaesthesia (bispectral index 50) showed drug administration declining with age consistent with clinical observations.

Conclusions: A PK-PD model for remimazolam was developed for a broad, diverse population. Dosing and target concentrations are proposed that are clinically useful for anaesthesia and sedation, especially for target-controlled infusion administration.

Keywords: ADME; CNS7054; antagonism; drug interaction; metabolism; pharmacodynamics; pharmacokinetics; remimazolam.

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Conflict of interest statement

Declarations of interest DJE is an editorial board member of Anesthesiology. He has received travel support from Becton Dickinson (Eysins, Switzerland). DJE, PC, JPVdB, and JVK share the departmental interests of MMRFS. TS is an employee of Paion, the European marketing authorisation holder of remimazolam. MMRFS’ research group or department received (over the last 3 years) research grants and consultancy fees from Masimo (Irvine, CA, USA), Becton Dickinson (Eysins, Switzerland), Fresenius-Kabi (Bad Homburg, Germany), Paion (Aachen, Germany), Medcaptain Europe (Andelst, The Netherlands), Baxter (Chicago, IL, USA), HanaPharm (Seoul, Republic of Korea). He receives royalties on intellectual property from Demed Medical (Sinaai, Belgium) and Ghent University (Ghent, Belgium).

Figures

Fig 1
Fig 1
Final pharmacokinetic and pharmacodynamic model structure. BIS, bispectral index; CL, clearance; ke0, first-order time constant; MOAA/S, Modified Observer's Assessment of Alertness and Sedation.
Fig 2
Fig 2
Simulations of effect-site TCI with the final model for sedation (MOAA/S 2 or 3) and anaesthesia (>90% MOAA/S 0), and predicted drug administration, concentrations and MOAA/S and BIS effects. BIS, bispectral index; Concentration for 50% drug effect (Ce50); MOAA/S, Modified Observer's Assessment of Alertness and Sedation; TCI, target-controlled infusion.
Fig 3
Fig 3
Simulations of effect-site TCI for sedation and anaesthesia comparing drug administration with recommendations from the literature. Concentration for 50% drug effect (Ce50); LOC, loss of consciousness; MOAA/S, Modified Observer's Assessment of Alertness and Sedation; TCI, target-controlled infusion.
Fig 4
Fig 4
Simulations of effect-site TCI for anaesthesia comparing drug administration for the Masui, Schuttler and Eisenried, and Zhou (without remifentanil or cumulative dose interaction or time-dependant clearance) models. BIS bispectral index; Concentration for 50% drug effect (Ce50); LOC, loss of consciousness.
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