Equilibration rate constant, ke0, to determine effect-site concentration for the Masui remimazolam population pharmacokinetic model in general anesthesia patients

Abstract

Effect-site concentration is widely used to determine drug dosage in anesthesia practice. To obtain effect-site concentration, a pharmacokinetic model with a corresponding equilibration rate constant between plasma and effect-site, k_e0, is necessary. Remimazolam, a novel short-acting benzodiazepine, has been approved as anesthetic/sedative. Recently, a remimazolam pharmacokinetic model has been published using a large dataset including wide range of subject characteristics (416 males and 246 females, age 18-93 years, total body weight 34-149 kg, height 133-204 cm, body mass index 14-61 kg m^-2, ASA physical status: I-IV, and Asian, White, American African, and 2 other races). This Masui model can be applicable to various patients, but a pharmacodynamic model including k_e0 was not developed simultaneously. A previous article has indicated that the time to peak effect of drug after its bolus should be used to determine k_e0 for a pharmacokinetic model without simultaneous development of corresponding pharmacodynamic model. The k_e0 value can be calculated using numerical analysis but not algebraic solution. We provide the detail method of the numerical analysis and a tool to have k_e0 value easily for the Masui remimazolam PK model. Additionally, we provide a multiple regression model to have k_e0 value for the PK model.

Keywords: Benzodiazepine; Effect-site concentration; Equilibration rate constant between plasma and effect-site; General anesthetic; Remimazolam.