A population pharmacokinetic model of remimazolam for general anesthesia and consideration of remimazolam dose in clinical practice

Abstract

Remimazolam besylate is a novel short-acting benzodiazepine. An appropriate pharmacokinetic model of remimazolam is desirable in anesthesia practice. The aim of the study was to develop a pharmacokinetic model using plasma samples from patients anesthetized with remimazolam. Influence of patient characteristics, context-sensitive decrement-times, and dose regimens were also examined. Data were obtained from four trials on patients, and seven trials on healthy volunteers. The characteristics of 416 male and 246 female subjects were as follows: age, 18-93years; body weight, 34-149kg; and American Society of Anesthesiologists physical status (ASA-PS), I-IV. 2231 arterial and 3200 venous samples were used for the final model. The equilibration rate constant between arterial plasma and effect-site was estimated using the concept of time to peak effect. The final model was used to generate context-sensitive decrement times and dose regimens for general anesthesia. A three-compartment model plus virtual venous compartment with allometric scaling of adjusted body weight (ABW), age, sex, and ASA-PS as covariates were selected as the final model. Elimination clearance was lower in males, and in subjects with higher ABW and ASA-PS scores. Approximately 10% or 20% higher dose rate was necessary in females than in males or ASA-PS I/II than III/IV patient. The context-sensitive half-time for effect-site concentration in a 55-year-old, 70-kg, 170-cm male or female ASA-PS I/II patient after > 6-h infusion was 16.7 or 15.9min. Remimazolam pharmacokinetic model for general anesthesia was successfully developed. ABW, ASA-PS, and sex has a considerable impact on the remimazolam concentration.