Newly Published
Perioperative Medicine  |   January 2020
Pharmacokinetics and Pharmacodynamics of Remimazolam (CNS 7056) after Continuous Infusion in Healthy Male Volunteers: Part I. Pharmacokinetics and Clinical Pharmacodynamics
Author Notes
  • Submitted for publication May 28, 2019. Accepted for publication December 1, 2019.
    Submitted for publication May 28, 2019. Accepted for publication December 1, 2019.×
  • Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).
    Supplemental Digital Content is available for this article. Direct URL citations appear in the printed text and are available in both the HTML and PDF versions of this article. Links to the digital files are provided in the HTML text of this article on the Journal’s Web site (www.anesthesiology.org).×
  • J.S. and A.E. contributed equally to this article.
    J.S. and A.E. contributed equally to this article.×
  • Parts of this work were presented at the Euroanaesthesia meeting, Copenhagen, Denmark, June 2–4, 2018.
    Parts of this work were presented at the Euroanaesthesia meeting, Copenhagen, Denmark, June 2–4, 2018.×
  • Correspondence: Address correspondence to Dr. Ihmsen: Anästhesiologische Klinik, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Krankenhausstrasse 12, 91054 Erlangen, Germany. harald.ihmsen@kfa.imed.uni-erlangen.de. Information on purchasing reprints may be found at www.anesthesiology.org or on the masthead page at the beginning of this issue. Anesthesiology’s articles are made freely accessible to all readers, for personal use only, 6 months from the cover date of the issue.
Article Information
Perioperative Medicine / Pharmacology
Perioperative Medicine   |   January 2020
Pharmacokinetics and Pharmacodynamics of Remimazolam (CNS 7056) after Continuous Infusion in Healthy Male Volunteers: Part I. Pharmacokinetics and Clinical Pharmacodynamics
Anesthesiology Newly Published on January 14, 2020. doi:https://doi.org/10.1097/ALN.0000000000003103
Anesthesiology Newly Published on January 14, 2020. doi:https://doi.org/10.1097/ALN.0000000000003103
Abstract

Editor’s Perspective:

What We Already Know about This Topic:

  • Remimazolam is rapidly metabolized to an inactive metabolite by tissue esterases

  • When administered as a 1-min infusion, it produced rapid onset and dose-dependent sedation at doses of 0.05 mg/kg and higher

  • Its pharmacokinetics when administered as a 1-min infusion was characterized by relatively high elimination clearance, a small steady-state volume of distribution, and a short elimination half-life

What This Article Tells Us That Is New:

  • Twenty adult male volunteers receiving remimazolam as continuous intravenous infusion at 5 mg/min for five min, then 3 mg/min for 15 min, and 1 mg/min for 15 min lost consciousness 5 ± 1 (mean ± SD) min after starting the infusion and were fully alert 19 ± 7 min after stopping it

  • Remizolam produced moderate hemodynamic effects and no clinically significant effect on cardiac repolarization

  • The disposition of remimazolam was characterized by a multicompartmental pharmacokinetic model with small distribution volumes and a high elimination clearance with small interindividual variability; its context-sensitive half time after a 4-h infusion was predicted to be 7 ± 2 min

Background: Remimazolam (CNS 7056) is a new ultra–short-acting benzodiazepine for intravenous sedation and anesthesia. Its pharmacokinetics and pharmacodynamics have been reported for bolus administration. This study aimed to investigate the pharmacokinetics and pharmacodynamics of remimazolam after continuous infusion.

Methods: Twenty healthy male volunteers (20 to 38 yr, 64 to 99 kg) received remimazolam as continuous intravenous infusion of 5 mg/min for 5 min, 3 mg/min for the next 15 min, and 1 mg/min for further 15 min. Pharmacokinetics of remimazolam and its metabolite were determined from arterial plasma concentrations. Sedation was assessed using the Modified Observer’s Assessment of Alertness and Sedation scale. Pharmacokinetic-pharmacodynamic modeling was performed by population analysis. Hemodynamics and the electrocardiogram were also investigated.

Results: Pharmacokinetics was best described by a three-compartment model for remimazolam and a two-compartment model with transit compartment for the metabolite. Remimazolam showed a high clearance (1.15 ± 0.12 l/min, mean ± SD), a small steady-state volume of distribution (35.4 ± 4.2 l) and a short terminal half-life (70 ± 10 min). The simulated context-sensitive halftime after an infusion of 4 h was 6.8 ± 2.4 min. Loss of consciousness was observed 5 ± 1 min after start, and full alertness was regained 19 ± 7 min after stop of infusion. Pharmacodynamics of Modified Observer’s Assessment of Alertness and Sedation score was best described by a sigmoid probability model with effect site compartment. The half-maximum effect site concentration for a Modified Observer’s Assessment of Alertness and Sedation score less than or equal to 1 was 695 ± 239 ng/ml. The equilibration half-time between central and effect compartment was 2.7 ± 0.6 min. Mean arterial blood pressure decreased by 24 ± 6%, and heart rate increased by 28 ± 15%. Spontaneous breathing was maintained throughout the study. There was no significant prolongation of the QT interval of the electrocardiogram observed.

Conclusions: Remimazolam was characterized by a pharmacokinetic–pharmacodynamic profile with fast onset, fast recovery, and moderate hemodynamic side effects.