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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 (n=11) or renal impairment (n=11) compared with matched healthy subjects (n=9 and n=12, respectively). The hepatic impairment trial was an open-label adaptive 'Reduced Design' trial, using a single bolus of remimazolam 0.1 mg kg-1 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 Cmax 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 Cmax 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. [ABSTRACT FROM AUTHOR]

Background: Target-controlled infusion (TCI) systems use pharmacokinetic (PK) models to predict the drug infusion rates necessary to achieve a desired target plasma or effect-site concentration. As new PK models are developed and implemented in TCI systems, there can be uncertainty as to which target concentrations are appropriate. Existing dose recommendations can serve as a point of reference to identify target concentrations suitable for clinical applications.Methods: Simulations of remifentanil TCI were performed using three PK models (Minto, Eleveld, and Kim). We sought to identify models and target concentrations for remifentanil administration in children, adult, older people, and severely obese individuals, consistent with the remifentanil product label. In a typical adult this is an induction dose of 0.5-1 μg kg-1 and starting maintenance infusion rate of 0.25 μg kg-1 min-1.Results: For the Minto, Eleveld, and Kim remifentanil models, a plasma target concentration of ∼ 4 ng ml-1 achieves drug administration consistent with product label recommended initial doses for all groups with minor exceptions. With effect-site targeting in older individuals, a target concentration of ∼2 ng ml-1 is required for induction and ∼4 ng ml-1 for starting maintenance to achieve drug dosages close to product label recommendations.Conclusions: We identified remifentanil TCI target concentrations that resulted in drug administration similar to product label dosing recommendations. This approach did not necessarily identify target concentrations that achieve desired clinical effect, only those that are consistent with the product label recommended doses. We estimate that plasma target concentrations of 3.1-5.3 ng ml-1 are suitable for initial dosing. [ABSTRACT FROM AUTHOR]

Objective neuromuscular monitoring remains the single most reliable method to ensure optimal perioperative neuromuscular management. Nevertheless, the prediction of clinical neuromuscular endpoints by means of Pharmacokinetic (PK) and Pharmacodynamic (PD) modelling has the potential to complement monitoring and improve perioperative neuromuscular management.s The present study aims to assess the performance of published Rocuronium PK/PD models in predicting intraoperative Train-of-four (TOF) ratios when benchmarked against electromyographic TOF measurements. Observational trial. Tertiary Belgian hospital, from August 2020 up to September 2021. Seventy-four patients undergoing general anaesthesia for elective surgery requiring the administration of rocuronium and subject to continuous EMG neuromuscular monitoring were included. PK/PD-simulated TOF ratios were plotted and synchronised with their measured electromyographic counterparts and their differences analysed by means of Predictive Error derivatives (Varvel criteria). Published rocuronium PK/PD models overestimated clinically registered TOF ratios. The models of Wierda, Szenohradszky, Cooper, Alvarez-Gomez and McCoy showed significant predictive consistency between themselves, displaying Median Absolute Performance Errors between 38% and 41%, and intra-individual differences (Wobble) between 14 and 15%. The Kleijn model outperformed the former with a lower Median Absolute Performance Error (16%, 95%CI [0.01; 57]) and Wobble (11%, 95%CI [0.01; 34]). All models displayed considerably wide 95% confidence intervals for all performance metrics, suggesting a significantly variable performance. Simulated TOF ratios based on published PK/PD models do not accurately predict real intraoperative TOF ratio dynamics. NCT04518761 (clinicaltrials.gov), registered on 19 August 2020. • Existing rocuronium PK/PD models innaccurately predict intraoperative TOF ratios. • These findings challenge the common rationale that "time after dose" is safe to exclude residual paralysis. • Quantitative neuromuscular monitoring is essential to assure an adequate recovery. [ABSTRACT FROM AUTHOR]