Population pharmacokinetic/pharmacodynamic modeling for remimazolam in the induction and maintenance of general anesthesia in healthy subjects and in surgical subjects - 24/09/20
, Cathrine Leonowens, PhD a , Vijay D. Ivaturi, PhD b , Lauren L. Lohmer, PhD a , Laura Curd, MS a , Joachim Ossig, PhD c, 1, Frank Schippers, MD c , Karl-Uwe Petersen, MD c , Thomas Stoehr, PhD c , Virginia Schmith, PhD a, ⁎ 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.
Le texte complet de cet article est disponible en PDF.Highlights |
• | PK-PD used to find remimazolam dose in general anesthesia for weight-based regimen. |
• | Most covariate effects were small and did not change the dosing recommendations. |
• | No dose adjustments required; but consider dose reduction in medically complex elderly patients. |
• | Consider dose reduction in ASA Class 3 patients with significant disease burden. |
Keywords : Pharmacokinetics, Pharmacodynamics, Remimazolam, General anesthesia, Post-surgical sedation, Simulations
Plan
Vol 66
Article 109899- novembre 2020 Retour au numéro
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