• Jie Zhou, Cathrine Leonowens, Vijay D Ivaturi, Lauren L Lohmer, Laura Curd, Joachim Ossig, Frank Schippers, Karl-Uwe Petersen, Thomas Stoehr, and Virginia Schmith.
• Nuventra Pharma Sciences, Durham, NC, USA. Electronic address: jzhou@nuventra.com.
• J Clin Anesth. 2020 Nov 1; 66: 109899.

Study ObjectiveTo evaluate factors affecting variability in response to remimazolam in general anesthesia.DesignPlasma 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.SettingGeneral anesthesia and post-surgical sedation.Patients689 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.InterventionsSerial plasma concentrations and BIS scores.MeasurementsStandard intra-operative monitoring.Main ResultsPopPK 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.ConclusionsIf 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.Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

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