A population pharmacodynamic Markov mixed‐effects model for determining remimazolam‐induced sedation when co‐administered with fentanyl in procedural sedation

Abstract

The clinical effects of remimazolam (an investigational, ultra-short acting benzodiazepine being studied in procedural sedation) were measured using the modified observer's alertness-sedation scale (MOAA/S). The objective of this analysis was to develop a population pharmacokinetic/pharmacodynamic (PopPK-PD) model to describe remimazolam-induced sedation with fentanyl over time in procedural sedation. MOAA/S from 10 clinical Phase 1-3 trials were pooled for analysis, where data were collected after administration of placebo or remimazolam with or without concomitant fentanyl. A Markov model described transition states for 35,356 MOAA/S-time observations from 1071 subjects. Effect-compartment models of remimazolam and fentanyl linked plasma concentrations to the Markov model, and drug effects were described using a synergistic Emax model. Simulations were performed to identify the optimal remimazolam-fentanyl combination doses in procedural sedation. Fentanyl showed synergistic effects with remimazolam in sedation. Increasing age was related to longer recovery from sedation. Patients with BMI > 25 kg/m 2 had 30% higher rates of distribution from plasma to the effect site (keo), indicating a slightly faster onset of sedation. Simulations showed that remimazolam 5 mg was more appropriate than 4 or 6 mg when administered with fentanyl 50 g.The model and simulations support that a combination of remimazolam 5 mg with fentanyl 50 g is an appropriate dosing regimen and the dose of remimazolam does not need to be changed in elderly patients, but some elderly patients may have a longer duration of sedation.

Remimazolam: Non-Clinical and Clinical Profile of a New Sedative/Anesthetic Agent

“…This is usually beneficial in both procedural sedation and anesthesia settings. The synergy with opioid analgesics has been clearly established for remimazolam (Bevans et al, 2017;Zhou et al, 2020a;Kops et al, 2021;Zhou et al, 2021).…”

“…The t 1/2,Ke0 parameter reflects the time required for the concentration in the effect compartment to reach 50% of the concentration in the plasma or the delay between cause and onset of effect. Calculated t 1/2,Ke0 values for remimazolam are usually reported in the range of 1–5 min ( Wiltshire et al, 2012 ; Zhou et al, 2020a ; Eisenried et al, 2020 ; Schüttler et al, 2020 ; Zhou et al, 2021 ). In a study of remimazolam tosylate, longer t 1/2,Ke0 values (=ln (2)/k e0 ) of 8.1 and 13.9 min were calculated for BIS monitoring and MOAA/S, respectively ( Zhou et al, 2018 ).…”

“…Modeling to establish dosing schedules, with concomitant analgesic, in phase III procedural sedation and anesthesia trials and the marketed products has been conducted ( Zhou et al, 2020a ; Zhou et al, 2020b ; Lohmer et al, 2020 ; Zhou et al, 2021 ). Dosing without correction for body weight is supported in procedural sedation ( Wiltshire et al, 2012 ; Zhou et al, 2020b ; Schüttler et al, 2020 ; Zhou et al, 2021 ).…”

Simulation of residual sedation effect of remimazolam: pharmacokinetic–pharmacodynamic simulation can be an additional standard anesthesia monitoring method

“…Effect-site concentration of remimazolam (µg/ml) simulations, as shown in this editorial, can help predict the future anesthetic effects even of soft drugs, such as remimazolam. Presently, several PK or PK-PD models have been published for remimazolam [15,18,19,21]; however, only a few models have a structure simple enough to be easily implemented in current simulators and to predict drug effects. Thus, more PK-PD clinical studies according to current clinical practice, such as flumazenil administration after remimazolam administration, are needed to increase the number of available PK-PD models; thus, the utility of PK-PD simulation is further recognized to become an additional standard monitoring procedure.…”

“…3). Additionally, aging causes changes in PK and PD of remimazolam [18,19], and the residual effects of remimazolam may be greater than that predicted by the Schüttler model constructed using data from younger volunteers.…”