Population pharmacokinetic/pharmacodynamic modeling for remimazolam in the induction and maintenance of general anesthesia in healthy subjects and in surgical subjects.

Study Objective: To evaluate factors affecting variability in response to remimazolam in general anesthesia.
Design: Plasma concentration-time data from 11 Phase 1-3 clinical trials were pooled for the population pharmacokinetic (popPK) analysis and concentration-bispectral index (BIS) data were pooled from 8 trials for popPK-PD analysis. A 3-compartment model with allometric exponents on clearance and volume described remimazolam concentrations over time. An effect compartment model with an inhibitory sigmoid Emax model was fit to the concentration-BIS data. Simulations were performed to assess sedation in general anesthesia and post-surgical sedation in healthy and sensitive populations.
Setting: General anesthesia and post-surgical sedation.
Patients: 689 subjects included in popPK and 604 subjects included in popPK-PD. Most subjects (>85%) were ASA Class 1 or 2, with the remaining subjects being ASA Class 3.
Interventions: Serial plasma concentrations and BIS scores.
Measurements: Standard intra-operative monitoring.
Main Results: PopPK model included an effect of extracorporeal circulation, ASA class, and sex on PK and a time-dependent clearance (~30% lower at 24 h) that was not related to cumulative dose. Co-administered remifentanil had a synergistic decrease in BIS with remimazolam. Remimazolam IC50 increased with cumulative dose. Onset was faster in overweight subjects and slower in Asian subjects. If using a weight-based regimen, simulations showed that remimazolam 6 mg/kg/h until loss of consciousness followed by 1 mg/kg/h during general anesthesia and 0.25 mg/kg/h for post-surgical sedation for up to 24 h is optimal, regardless of ASA class or sensitivity of subjects.
Conclusions: If using a weight-based regimen, results illustrated an appropriate regimen of remimazolam for general anesthesia and post-surgical sedation in general and sensitive populations, although lower doses can be considered in elderly patients with a significant disease burden or in ASA Class 3 patients. The time-dependent change in clearance is not clinically relevant for up to 24 h.
Competing Interests: Declaration of competing interest J Zhou, C Leonowens, V Ivaturi, L Lohmer, L Curd, and V Schmith, are paid consultants for Paion AG. J Ossig, F Schippers, K Petersen, and T Stoehr are/were employees of Paion GmbH.
(Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)