Population pharmacokinetic/pharmacodynamic modeling for remimazolam in the induction and maintenance of general anesthesia in healthy subjects and in surgical subjects
Jie Zhou, Cathrine Leonowens, Vijay Ivaturi, Lauren L. Lohmer, Laura Curd, Joachim Ossig, Frank Schippers, Karl‐Uwe Petersen, Thomas Stoehr, Virginia D. Schmith
Abstract
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.