Jie Zhou1, Cathrine Leonowens2, Vijay D Ivaturi3, Lauren L Lohmer4, Laura Curd5, Joachim Ossig6, Frank Schippers7, Karl-Uwe Petersen8, Thomas Stoehr9, Virginia Schmith10. 1. Nuventra Pharma Sciences, Durham, NC, USA. Electronic address: jzhou@nuventra.com. 2. Nuventra Pharma Sciences, Durham, NC, USA. Electronic address: cleonowens@nuventra.com. 3. Center for Translational Medicine, University of Maryland School of Pharmacy Baltimore, USA. Electronic address: vivaturi@rx.umaryland.edu. 4. Nuventra Pharma Sciences, Durham, NC, USA. Electronic address: llohmer@nuventra.com. 5. Nuventra Pharma Sciences, Durham, NC, USA. Electronic address: lcurd@nuventra.com. 6. PAION UK Ltd, Cambridge, England, United Kingdom of Great Britain and Northern Ireland. 7. PAION UK Ltd, Cambridge, England, United Kingdom of Great Britain and Northern Ireland. Electronic address: f.schippers@paion.com. 8. PAION UK Ltd, Cambridge, England, United Kingdom of Great Britain and Northern Ireland. Electronic address: ku.petersen@paion.com. 9. PAION UK Ltd, Cambridge, England, United Kingdom of Great Britain and Northern Ireland. Electronic address: t.stoehr@paion.com. 10. Nuventra Pharma Sciences, Durham, NC, USA. Electronic address: gschmith@nuventra.com.
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.
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.
Authors: Remco Vellinga; Beatrijs I Valk; Anthony R Absalom; Michel M R F Struys; Clemens R M Barends Journal: J Clin Med Date: 2022-06-17 Impact factor: 4.964
Authors: Jie Zhou; Laura Curd; Lauren L Lohmer; Joachim Ossig; Frank Schippers; Thomas Stoehr; Virginia Schmith Journal: Clin Transl Sci Date: 2020-10-12 Impact factor: 4.689
Authors: Jie Zhou; Laura Curd; Lauren R L Lohmer; Natalie Delpratt; Joachim Ossig; Frank Schippers; Thomas Stoehr; Virginia D Schmith Journal: Clin Transl Sci Date: 2021-04-09 Impact factor: 4.689