Predictivity of in vitro non-clinical cardiac contractility assays for inotropic effects in humans – A Literature Search

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    Abstract

    Adverse drug effects on the cardiovascular system is a major cause of compound attrition throughout compound discovery and development. There are many ways by which drugs can affect the cardiovascular system, including effects on the electrocardiogram, vascular resistance, heart rate and the force of contraction of the heart (inotropy). Compounds that increase the force of contraction of the heart can be harmful in patients with ischemic heart disease, whilst negative inotropes can induce symptoms of heart failure. There is a range of non-clinical in vitro and in vivo assays used to detect inotropic effects of drugs. We have conducted a literature review of the in vitro assays and compared the findings from these with known effects on cardiac contractility in man. There was a wide variety of assays used, ranging from perfuse whole hearts to isolated regions of the heart (papillary muscle, ventricle and atria), which were removed from a number of species (cat, guinea pig, rabbit and rat). We conducted two analyses. The first was investigating the concordance of the findings from the in vitro assays at any concentration with those observed in man (an assessment of hazard identification) and the second was the concordance of the in vitro findings at concentrations tested up to 10-fold higher than those tested in the clinic. We found that when used as a hazard identification tool, the available assays had good sensitivity (88%), although the specificity was not so good (60%), but when used as a risk management tool the sensitivity was considerable reduced (sensitivity 58 -70% and specificity 60%).These data would suggest that the available in vitro assays can be used as hazard identification tools for adverse drug effects on cardiac contractility, but there is a need for new assays to better predict the exposures in man that may cause a change in cardiac contractility and therefore better predict the likely therapeutic index of compounds prior to nomination of compounds for clinical development.
    Original languageEnglish
    Pages (from-to)62-69
    Number of pages8
    JournalJournal of Pharmacological and Toxicological Methods
    Volume75
    Early online date27 May 2015
    DOIs
    Publication statusPublished - 2015

    Fingerprint

    Assays
    Cardiovascular System
    Pharmaceutical Preparations
    Cardiovascular system
    Hazards
    Papillary Muscles
    Risk Management
    Heart Atria
    Vascular Resistance
    Myocardial Ischemia
    Myocardium
    Electrocardiography
    Guinea Pigs
    Cats
    Heart Failure
    Heart Rate
    In Vitro Techniques
    Risk management
    Rabbits
    Muscle

    Bibliographical note

    NOTICE: this is the author’s version of a work that was accepted for publication in the Journal of Pharmacological and Toxicological Methods. Changes resulting from the publishing process, such as peer review, editing, corrections, structural formatting, and other quality control mechanisms may not be reflected in this document. Changes may have been made to this work since it was submitted for publication. A definitive version was subsequently published in the Journal of Pharmacological and Toxicological Methods (Vol 75, (2015)]. DOI: 10.1016/j.vascn.2015.05.009 .

    © 2015, Elsevier. Licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International http://creativecommons.org/licenses/by-nc-nd/4.0/

    Funder

    NC3Rs and Innovate UK (Grants 131722 & 710533).

    Keywords

    • drugs
    • inotropic effects
    • cardiovascular system
    • in vitro assays

    Cite this

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    abstract = "Adverse drug effects on the cardiovascular system is a major cause of compound attrition throughout compound discovery and development. There are many ways by which drugs can affect the cardiovascular system, including effects on the electrocardiogram, vascular resistance, heart rate and the force of contraction of the heart (inotropy). Compounds that increase the force of contraction of the heart can be harmful in patients with ischemic heart disease, whilst negative inotropes can induce symptoms of heart failure. There is a range of non-clinical in vitro and in vivo assays used to detect inotropic effects of drugs. We have conducted a literature review of the in vitro assays and compared the findings from these with known effects on cardiac contractility in man. There was a wide variety of assays used, ranging from perfuse whole hearts to isolated regions of the heart (papillary muscle, ventricle and atria), which were removed from a number of species (cat, guinea pig, rabbit and rat). We conducted two analyses. The first was investigating the concordance of the findings from the in vitro assays at any concentration with those observed in man (an assessment of hazard identification) and the second was the concordance of the in vitro findings at concentrations tested up to 10-fold higher than those tested in the clinic. We found that when used as a hazard identification tool, the available assays had good sensitivity (88{\%}), although the specificity was not so good (60{\%}), but when used as a risk management tool the sensitivity was considerable reduced (sensitivity 58 -70{\%} and specificity 60{\%}).These data would suggest that the available in vitro assays can be used as hazard identification tools for adverse drug effects on cardiac contractility, but there is a need for new assays to better predict the exposures in man that may cause a change in cardiac contractility and therefore better predict the likely therapeutic index of compounds prior to nomination of compounds for clinical development.",
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