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

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.