Pharma / Biotech

Pharmacokinetics and Pharmacodynamics of Remimazolam (CNS 7056) after Continuous Infusion in Healthy Male Volunteers: Part II. Pharmacodynamics of Electroencephalogram Effects.



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Pharmacokinetics and Pharmacodynamics of Remimazolam (CNS 7056) after Continuous Infusion in Healthy Male Volunteers: Part II. Pharmacodynamics of Electroencephalogram Effects.

Anesthesiology. 2020 Jan 14;:

Authors: Eisenried A, Schüttler J, Lerch M, Ihmsen H, Jeleazcov C

Abstract
WHAT WE ALREADY KNOW ABOUT THIS TOPIC: Intravenously administered remimazolam can produce deep sedation quickly from which the patient recovers rapidly due, in part, to its relatively high clearance by tissue esterasesElectroencephalogram measures with a significant correlation to sedation scales provide a continuous noninvasive method for quantifying central nervous system drug effects without the need to stimulate the patient WHAT THIS ARTICLE TELLS US THAT IS NEW: Electroencephalogram changes during remimazolam infusion in 20 adult male volunteers were characterized by an initial increase in the beta frequency band and a late increase in the delta frequency bandBeta ratio had a monotonic relationship to Modified Observer’s Assessment of Alertness and Sedation scores and could be modeled using a standard sigmoid Emax pharmacodynamic modelThe standard sigmoid Emax model failed to describe the time course of the Narcotrend Index appropriately; it was necessary to extend the model by adding a second sigmoid term with a second effect site concentration BACKGROUND:: Remimazolam (CNS 7056) is a new ultra-short acting benzodiazepine for IV sedation. This study aimed to investigate the electroencephalogram (EEG) pharmacodynamics of remimazolam infusion.
METHODS: Twenty healthy male volunteers received remimazolam as continuous IV infusion of 5 mg/min for 5 min, 3 mg/min for the next 15 min, and 1 mg/min for further 15 min. Continuous EEG monitoring was performed by a neurophysiologic system with electrodes placed at F3, F4, C3, C4, O1, O2, Cz, and Fp1 (10/20 system) and using the Narcotrend Index. Sedation was assessed clinically by using the Modified Observer’s Assessment of Alertness and Sedation scale. Pharmacodynamic models were developed for selected EEG variables and Narcotrend Index.
RESULTS: EEG changes during remimazolam infusion were characterized by an initial increase in beta frequency band and a late increase in delta frequency band. The EEG beta ratio showed a prediction probability of Modified Observer’s Assessment of Alertness and Sedation score of 0.79, and could be modeled successfully using a standard sigmoid Emax model. Narcotrend Index showed a prediction probability of Modified Observer’s Assessment of Alertness and Sedation score of 0.74. The time course of Narcotrend Index was described by an extended sigmoid Emax model with two sigmoid terms and different plasma-effect equilibration times.
CONCLUSIONS: Beta ratio was identified as a suitable EEG variable for monitoring remimazolam sedation. Narcotrend Index appeared less suitable than the beta ratio for monitoring the sedative effect if remimazolam is administered alone.

PMID: 31972657 [PubMed – as supplied by publisher]

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