Stereoselective ketamine effect on cardiac output: a population pharmacokinetic/pharmacodynamic modelling study in healthy volunteers.

Tytuł:: Stereoselective ketamine effect on cardiac output: a population pharmacokinetic/pharmacodynamic modelling study in healthy volunteers.
Autorzy:: Kamp J; Department of Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands.
van Velzen M; Department of Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands.
Aarts L; Department of Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands.
Niesters M; Department of Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands.
Dahan A; Department of Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands. Electronic address: .
Olofsen E; Department of Anesthesiology, Leiden University Medical Center, Leiden, the Netherlands.
Źródło:: British journal of anaesthesia [Br J Anaesth] 2021 Jul; Vol. 127 (1), pp. 23-31. Date of Electronic Publication: 2021 Apr 22.
Typ publikacji:: Journal Article; Randomized Controlled Trial
Język:: English
Imprint Name(s):: Publication: 2018- : [London] : Elsevier
Original Publication: London, Eng. [etc.]
MeSH Terms:: Anesthetics, Dissociative/*chemistry
Anesthetics, Dissociative/*pharmacokinetics
Cardiac Output/*drug effects
Ketamine/*chemistry
Ketamine/*pharmacokinetics
Adult ; Cardiac Output/physiology ; Cross-Over Studies ; Dose-Response Relationship, Drug ; Double-Blind Method ; Healthy Volunteers ; Humans ; Male ; Stereoisomerism ; Young Adult
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Contributed Indexing:: Keywords: NONMEM; cardiac output; hydroxynorketamine; ketamine; metabolomics; modeling; norketamine; stereoselectivity
Substance Nomenclature:: 0 (Anesthetics, Dissociative)
690G0D6V8H (Ketamine)
Entry Date(s):: Date Created: 20210426 Date Completed: 20210721 Latest Revision: 20210721
Update Code:: 20240104
PubMed Central ID:: PMC8258972
DOI:: 10.1016/j.bja.2021.02.034
PMID:: 33896589
: Czasopismo naukowe

Background: Ketamine has cardiac excitatory side-effects. Currently, data on the effects of ketamine and metabolite concentrations on cardiac output are scarce. We therefore developed a pharmacodynamic model derived from data from a randomised clinical trial. The current study is part of a larger clinical study evaluating the potential mitigating effect of sodium nitroprusside on the psychedelic effects of ketamine.
Methods: Twenty healthy male subjects received escalating esketamine and racemic ketamine doses in combination with either placebo or sodium nitroprusside on four visits: (i) esketamine and placebo, (ii) esketamine and sodium nitroprusside, (iii) racemic ketamine and placebo, and (iv) racemic ketamine and sodium nitroprusside. During each visit, arterial blood samples were obtained and cardiac output was measured. Nonlinear mixed-effect modelling was used to analyse the cardiac output time-series data. Ketamine metabolites were added to the model in a sequential manner to evaluate the effects of metabolites.
Results: A model including an S-ketamine and S-norketamine effect best described the data. Ketamine increased cardiac output, whereas modelling revealed that S-norketamine decreased cardiac output. No significant effects were detected for R-ketamine, metabolites other than S-norketamine, or sodium nitroprusside on cardiac output.
Conclusions: S-Ketamine, but not R-ketamine, increased cardiac output in a dose-dependent manner. In contrast to S-ketamine, its metabolite S-norketamine reduced cardiac excitation in a dose-dependent manner.
Clinical Trial Registration: Dutch Cochrane Center 5359.
Competing Interests: Declarations of interest The authors declare that they have no conflicts of interest.
(Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Comment in: Br J Anaesth. 2021 Jul;127(1):1-2. (PMID: 33965204)

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