hERG Inhibitors with Similar Potency But Different Binding Kinetics Do Not Pose the Same Proarrhythmic Risk: Implications for Drug Safety Assessment.
Drug Mode of Action and hERG-Related Safety Introduction Since the discovery of the link that exists between drug-induced hERG inhibition and Torsade de Pointes (TdP), extreme attention has been given to avoid new drugs inhibiting this channel. hERG inhibition is routinely screened for in new drugs...
| Publicado en: | Journal of Cardiovascular Electrophysiology Vol. 25; no. 2; pp. 197 - 208 |
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| Autores principales: | , , , , |
| Formato: | equations & formulas research tables/charts Journal Article |
| Publicado: |
Wiley-Blackwell
Feb2014
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=104023657&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 104023657 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 10453873 GSB jtl: Journal of Cardiovascular Electrophysiology issn: 10453873 maglogo: Y pubinfo: dt: Feb2014 vid: 25 iid: 2 pid: 480 pub: Wiley-Blackwell place: Malden, Massachusetts artinfo: ui: 104023657 94397709 10.1111/jce.12289 NLM24118558 104023657 ppf: 197 ppct: 11 formats: fmt: @attributes: type: P tig: atl: hERG Inhibitors with Similar Potency But Different Binding Kinetics Do Not Pose the Same Proarrhythmic Risk: Implications for Drug Safety Assessment. aug: au: Veroli, Giovanni Y. Davies, Mark R. Zhang, Henggui Abi-Gerges, Najah Boyett, Mark R. affil: Institute of Cardiovascular Sciences, University of Manchester; Translational Safety, Drug Safety & Metabolism sug: subj: Potassium Membrane Proteins Antagonists and Inhibitors Membrane Proteins Drug Effects Kinetics Arrhythmia Risk Factors Drugs, Investigational Administration and Dosage Drugs, Investigational Adverse Effects Animal Studies Dogs Models, Statistical Descriptive Statistics Action Potentials Simulations Data Analysis Software Electrophysiology Funding Source ab: Drug Mode of Action and hERG-Related Safety Introduction Since the discovery of the link that exists between drug-induced hERG inhibition and Torsade de Pointes (TdP), extreme attention has been given to avoid new drugs inhibiting this channel. hERG inhibition is routinely screened for in new drugs and, typically, IC50 values are compared to projected plasma concentrations to define a safety margin. Methods and Results We aimed to show that drugs with similar hERG potency are not uniformly pro-arrhythmic-this depends on the drug binding kinetics and mode of action (trapped or not) rather than the IC50 value only. We used a mathematical model of hERG and its related encoded current IKr to simulate drug binding in different configurations. Expression systems mimicking the screening process were first investigated. hERG model was then incorporated into a canine action potential (AP) and tissue model to study the impact of drug binding configurations on AP and pseudo-ECG (QT interval prolongation). Our data show that: (1) trapped and not trapped configurations and different binding kinetics could be identified during hERG screening; (2) slow binding, not trapped drugs, induced less AP prolongation and minimal QT interval prolongation (4.7%) at a concentration equal to the IC50 whereas maximal pro-arrhythmic risk was observed for trapped drugs at the same concentration (QT interval prolongation, 23.1%). Conclusion Our study demonstrates the need for screening for hERG binding configurations rather than potency alone. It also demonstrates the potential link between hERG, drug mode of action and TdP, and the need to question the current regulatory guidance. pubtype: Academic Journal doctype: equations & formulas research tables/charts Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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