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...

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Veröffentlicht in:Journal of cardiovascular electrophysiology 2014-02, Vol.25 (2), p.197-207
Hauptverfasser: DI VEROLI, GIOVANNI Y., DAVIES, MARK R., ZHANG, HENGGUI, ABI-GERGES, NAJAH, BOYETT, MARK R.
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container_issue 2
container_start_page 197
container_title Journal of cardiovascular electrophysiology
container_volume 25
creator DI VEROLI, GIOVANNI Y.
DAVIES, MARK R.
ZHANG, HENGGUI
ABI-GERGES, NAJAH
BOYETT, MARK R.
description 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.
doi_str_mv 10.1111/jce.12289
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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.</description><identifier>ISSN: 1045-3873</identifier><identifier>EISSN: 1540-8167</identifier><identifier>DOI: 10.1111/jce.12289</identifier><identifier>PMID: 24118558</identifier><language>eng</language><publisher>United States: Blackwell Publishing Ltd</publisher><subject>Animals ; Arrhythmias, Cardiac - chemically induced ; Arrhythmias, Cardiac - metabolism ; Binding Sites ; Calcium Channel Blockers - administration &amp; dosage ; Calcium Channel Blockers - adverse effects ; Cardiac arrhythmia ; computational modeling ; Computer Simulation ; Dogs ; Dose-Response Relationship, Drug ; drug binding kinetics ; Drug Evaluation, Preclinical - methods ; Drug therapy ; ERG1 Potassium Channel ; Ether-A-Go-Go Potassium Channels - antagonists &amp; inhibitors ; Ether-A-Go-Go Potassium Channels - metabolism ; hERG ion channel ; Humans ; Kinetics ; Mathematical models ; Models, Cardiovascular ; Models, Chemical ; pro-arrhythmia ; Protein Binding ; QT prolongation ; Therapeutic Equivalency ; Torsades de Pointes ; ventricular tachycardia</subject><ispartof>Journal of cardiovascular electrophysiology, 2014-02, Vol.25 (2), p.197-207</ispartof><rights>2013 Wiley Periodicals, Inc.</rights><rights>Journal compilation © 2014 Wiley Periodicals, Inc.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c4179-37f6ee2077dae5d8dbdb1556757b839cb0ac18c79a9b64fcd4c57aedb44e6cc03</citedby><cites>FETCH-LOGICAL-c4179-37f6ee2077dae5d8dbdb1556757b839cb0ac18c79a9b64fcd4c57aedb44e6cc03</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1111%2Fjce.12289$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1111%2Fjce.12289$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,778,782,1414,27907,27908,45557,45558</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24118558$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>DI VEROLI, GIOVANNI Y.</creatorcontrib><creatorcontrib>DAVIES, MARK R.</creatorcontrib><creatorcontrib>ZHANG, HENGGUI</creatorcontrib><creatorcontrib>ABI-GERGES, NAJAH</creatorcontrib><creatorcontrib>BOYETT, MARK R.</creatorcontrib><title>hERG Inhibitors with Similar Potency But Different Binding Kinetics Do Not Pose the Same Proarrhythmic Risk: Implications for Drug Safety Assessment</title><title>Journal of cardiovascular electrophysiology</title><addtitle>J Cardiovasc Electrophysiol</addtitle><description>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. 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DAVIES, MARK R. ; ZHANG, HENGGUI ; ABI-GERGES, NAJAH ; BOYETT, MARK R.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c4179-37f6ee2077dae5d8dbdb1556757b839cb0ac18c79a9b64fcd4c57aedb44e6cc03</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Arrhythmias, Cardiac - chemically induced</topic><topic>Arrhythmias, Cardiac - metabolism</topic><topic>Binding Sites</topic><topic>Calcium Channel Blockers - administration &amp; dosage</topic><topic>Calcium Channel Blockers - adverse effects</topic><topic>Cardiac arrhythmia</topic><topic>computational modeling</topic><topic>Computer Simulation</topic><topic>Dogs</topic><topic>Dose-Response Relationship, Drug</topic><topic>drug binding kinetics</topic><topic>Drug Evaluation, Preclinical - methods</topic><topic>Drug therapy</topic><topic>ERG1 Potassium Channel</topic><topic>Ether-A-Go-Go Potassium Channels - antagonists &amp; inhibitors</topic><topic>Ether-A-Go-Go Potassium Channels - metabolism</topic><topic>hERG ion channel</topic><topic>Humans</topic><topic>Kinetics</topic><topic>Mathematical models</topic><topic>Models, Cardiovascular</topic><topic>Models, Chemical</topic><topic>pro-arrhythmia</topic><topic>Protein Binding</topic><topic>QT prolongation</topic><topic>Therapeutic Equivalency</topic><topic>Torsades de Pointes</topic><topic>ventricular tachycardia</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>DI VEROLI, GIOVANNI Y.</creatorcontrib><creatorcontrib>DAVIES, MARK R.</creatorcontrib><creatorcontrib>ZHANG, HENGGUI</creatorcontrib><creatorcontrib>ABI-GERGES, NAJAH</creatorcontrib><creatorcontrib>BOYETT, MARK R.</creatorcontrib><collection>Istex</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium &amp; 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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.</abstract><cop>United States</cop><pub>Blackwell Publishing Ltd</pub><pmid>24118558</pmid><doi>10.1111/jce.12289</doi><tpages>11</tpages></addata></record>
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subjects Animals
Arrhythmias, Cardiac - chemically induced
Arrhythmias, Cardiac - metabolism
Binding Sites
Calcium Channel Blockers - administration & dosage
Calcium Channel Blockers - adverse effects
Cardiac arrhythmia
computational modeling
Computer Simulation
Dogs
Dose-Response Relationship, Drug
drug binding kinetics
Drug Evaluation, Preclinical - methods
Drug therapy
ERG1 Potassium Channel
Ether-A-Go-Go Potassium Channels - antagonists & inhibitors
Ether-A-Go-Go Potassium Channels - metabolism
hERG ion channel
Humans
Kinetics
Mathematical models
Models, Cardiovascular
Models, Chemical
pro-arrhythmia
Protein Binding
QT prolongation
Therapeutic Equivalency
Torsades de Pointes
ventricular tachycardia
title hERG Inhibitors with Similar Potency But Different Binding Kinetics Do Not Pose the Same Proarrhythmic Risk: Implications for Drug Safety Assessment
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