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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 Assessment of Awareness/Sedation Scale (MOAA/S). The objective of this analysis was to develop a population pharmacokinetic/pharmacodynamic model to describe remimazolam-induced sedation with fentanyl over time in procedural sedation. MOAA/S from 10 clinical phase I-III 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 maximum effect (E_max ) 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 body mass index greater than 25 kg/m² 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 μg. The model and simulations support that a combination of remimazolam 5 mg with fentanyl 50 μg 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.

SUBMITTER: Zhou J

PROVIDER: S-EPMC8301564 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTo improve patient tolerability and satisfaction as well as minimize complications, procedural sedation has been widely used. Propofol is the most widely used agent for induction of anesthesia and sedation by anesthesiologists. With a different mechanism compared to propofol, remimazolam is a new short-acting GABA-A receptor agonist. It is an ester-based benzodiazepine. This meta-analysis aims to clarify the efficacy and safety of remimazolam versus propofol for procedure sedation.MethodsElectronic databases were searched for randomized controlled trials (RCTs) comparing efficacy or safety of remimazolam versus propofol. Meta-analysis were conducted using RStudio with "metafor" package with random-effects model.ResultsA total of twelve RCTs were included in the meta-analysis. The pooled results demonstrated that patients with remimazolam for procedural sedation had lower risk of bradycardia (OR 0.28, 95% CI [0.14-0.57]), hypotension (OR 0.26, 95% CI [0.22-0.32]), and respiratory depression (OR 0.22, 95% CI [0.14-0.36]). There was no difference in the risk of developing postoperative nausea and vomiting (PONV) (OR 0.65, 95% CI [0.15-2.79]) and dizziness (OR 0.93, 95% CI [0.53-1.61]) between the remimazolam and propofol groups. Using remimazolam for procedural sedation is significantly associated with less injection pain compared to propofol (OR 0.06, 95% CI [0.03-0.13]). Regarding the sedation efficacy, there was no difference in sedation success rate or time to loss of consciousness, recover and discharge between the remimazolam and the propofol groups.ConclusionsBased on our meta-analysis, patients receiving procedural sedation with remimazolam had lower risk of bradycardia, hypotension, respiratory depression and injection pain compared with propofol. On the other hand, there was no difference in sedation success rate, risk of PONV, dizziness, time to LOC, recovery and discharge between these two sedatives.Prospero registration numberCRD42022362950.

Project description:Background and study aims Remimazolam is an ultra-short acting, fast onset/fast offset benzodiazepine for intravenous use in procedural sedation, general anesthesia, and Intensive Care Unit sedation. The aim of this work was to compare the efficacy of remimazolam versus midazolam dosed according to medical practice (real-world midazolam) and midazolam dosed according to US prescribing information (on-label midazolam) for procedural sedation. Patients and methods This post hoc analysis was performed using integrated data from three randomized, placebo, and active (midazolam) controlled, phase 3 clinical trials in patients undergoing colonoscopy and bronchoscopy. Statistical comparisons between treatment groups, without adjustment for potential confounding factors, were exploratory and observational in nature. Results The mean ± SD dose of midazolam in the real-world midazolam group was 6.2 ± 3.1 mg, compared with 3.5 ± 1.5 mg in the on-label midazolam group. remimazolam showed significantly shorter time from first dose to start of procedure (median 3 minutes) compared to on-label midazolam (median 8 minutes). Recovery time from end of procedure to fully alert was significantly shorter for remimazolam (median 6 minutes) than real-world midazolam (median 14 minutes), enabling earlier transfer of patients from the procedure room to the recovery area with a lower requirement for patient monitoring. The onset and recovery times with remimazolam showed significantly less inter-patient variability than with on-label midazolam and real-world midazolam, respectively. Patients treated with remimazolam received significantly less fentanyl for analgesia (78.2 ± 28.4 µg) than did those treated with real-world midazolam (113.6 ± 60.1 µg) and on-label midazolam (92.5 ± 40.0 µg). Conclusions Remimazolam offers advantages over midazolam in terms of faster recovery and less fentanyl requirement, which may facilitate increased procedural throughput in clinical practice.

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

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