Population Pharmacokinetics of Remimazolam in Procedural Sedation With Nonhomogeneously Mixed Arterial and Venous Concentrations

Zhou, Jie; Curd, Laura; Lohmer, Lauren L.; Ossig, Joachim; Schippers, Frank; Stoehr, Thomas; Schmith, Virginia D.

doi:10.1111/cts.12875

Cited by 23 publications

(18 citation statements)

References 15 publications

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“…Remimazolam Exposure: Empiric Bayes Estimates (EBE) of PK parameters from a previously developed popPK model 19 were used to predict remimazolam Cp at the time of each RCMOAAS score for 319 subjects with Cp data. In subjects with PD (but no PK) data, individual PK parameters were simulated based on population PK parameters including relevant covariates forpredictions of Cp at the time of each MOAA/S score.…”

Section: General Modeling Methods: Nonmem ® Version 73 (Icon Developmentioning

confidence: 99%

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

Zhou¹,

Curd²,

Lohmer³

et al. 2021

Clinical Translational Sci

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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.

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Section: General Modeling Methods: Nonmem ® Version 73 (Icon Developmentioning

confidence: 99%

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

Zhou¹,

Curd²,

Lohmer³

et al. 2021

Clinical Translational Sci

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“…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 ).…”

Section: Remimazolammentioning

confidence: 99%

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

Kilpatrick¹

2021

Front. Pharmacol.

146

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A program to identify novel intravenous sedatives with a short and predictable duration of action was initiated in the late 1990’s by Glaxo Wellcome. The program focussed on the identification of ester-based benzodiazepine derivatives that are rapidly broken down by esterases. Remimazolam was identified as one of the lead compounds. The project at Glaxo was shelved for strategic reasons at the late lead optimization stage. Via the GSK ventures initiative, the program was acquired by the small biotechnology company, TheraSci, and, through successive acquisitions, developed as the besylate salt at CeNeS and PAION. The development of remimazolam besylate has been slow by industry standards, primarily because of the resource limitations of these small companies. It has, however, recently been approved for anesthesia in Japan and South Korea, procedural sedation in the United States, China, and Europe, and for compassionate use in intensive care unit sedation in Belgium. A second development program of remimazolam was later initiated in China, using a slightly different salt form, remimazolam tosylate. This salt form of the compound has also recently been approved for procedural sedation in China. Remimazolam has the pharmacological profile of a classical benzodiazepine, such as midazolam, but is differentiated from other intravenous benzodiazepines by its rapid conversion to an inactive metabolite resulting in a short onset/offset profile. It is differentiated from other intravenous hypnotic agents, such as propofol, by its low liability for cardiovascular depression, respiratory depression, and injection pain. The benzodiazepine antagonist flumazenil can reverse the effects of remimazolam in case of adverse events and further shorten recovery times. The aim of this review is to provide an analysis of, and perspective on, published non-clinical and clinical information on 1) the pharmacology, metabolism, pharmacokinetics, and pharmacodynamic profile of remimazolam, 2) the profile of remimazolam compared with established agents, 3) gaps in the current understanding of remimazolam, 4) the compound’s discovery and development process and 5) likely future developments in the clinical use of remimazolam.

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“…A similar difference has been described by another PK/PD model for remimazolam. 18 The PK of the remimazolam metabolite, CNS7054, was not described in the population PK model. Notable differences were revealed when the concentration time profiles for CNS7054 were visually inspected (Fig.…”

Section: Recirculatory Pharmacokinetic Modelmentioning

confidence: 99%

Pharmacokinetic properties of remimazolam in subjects with hepatic or renal impairment

Stöhr

Colin

Ossig

et al. 2021

British Journal of Anaesthesia

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110

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Background: Remimazolam is a new benzodiazepine for procedural sedation and general anaesthesia. The aim of this study was to characterise its pharmacokinetic properties and safety in renally and hepatically impaired subjects. Methods: Two separate trials were conducted in patients with hepatic (n¼11) or renal impairment (n¼11) compared with matched healthy subjects (n¼9 and n¼12, respectively). The hepatic impairment trial was an open-label adaptive 'Reduced Design' trial, using a single bolus of remimazolam 0.1 mg kg À1 i.v., whereas the renal impairment trial was an open-label trial of a single bolus dose of remimazolam 1.5 mg i.v. Remimazolam plasma concentrations over time were analysed by population pharmacokinetic modelling. Results: Remimazolam pharmacokinetic properties were adequately described by a three-compartment, recirculatory model. Exposure in subjects with severe hepatic impairment was 38.1% higher (i.e. clearance was 38.1% lower) compared with healthy volunteers. This increase caused a slightly delayed recovery (8.0 min for healthy, 12.1 min for moderate, and 16.7 min for severe hepatic impairment). With renal impairment, plasma clearance was comparable with that measured in healthy subjects. Simulations of C max after a bolus dose of 10 mg showed no relevant impact of hepatic or renal impairment. The overall incidence of adverse events was low, and all adverse events were mild. Conclusions: As C max after a remimazolam bolus i.v. was not affected by hepatic or renal impairment, no dose adjustments are required. No unexpected adverse events related to remimazolam were seen in subjects with renal or hepatic impairment. Clinical trial registration: Hepatic impairment trial: ClinicalTrials.gov, NCT01790607 (https://clinicaltrials.gov/ct2/show/ NCT01790607). Renal impairment trial: EudraCT Number: 2014-004575-23.

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Population Pharmacokinetics of Remimazolam in Procedural Sedation With Nonhomogeneously Mixed Arterial and Venous Concentrations

Cited by 23 publications

References 15 publications

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

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

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

Pharmacokinetic properties of remimazolam in subjects with hepatic or renal impairment

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