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 |
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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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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.</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 & 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</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. It also demonstrates the potential link between hERG, drug mode of action and TdP, and the need to question the current regulatory guidance.</description><subject>Animals</subject><subject>Arrhythmias, Cardiac - chemically induced</subject><subject>Arrhythmias, Cardiac - metabolism</subject><subject>Binding Sites</subject><subject>Calcium Channel Blockers - administration & dosage</subject><subject>Calcium Channel Blockers - adverse effects</subject><subject>Cardiac arrhythmia</subject><subject>computational modeling</subject><subject>Computer Simulation</subject><subject>Dogs</subject><subject>Dose-Response Relationship, Drug</subject><subject>drug binding kinetics</subject><subject>Drug Evaluation, Preclinical - methods</subject><subject>Drug therapy</subject><subject>ERG1 Potassium Channel</subject><subject>Ether-A-Go-Go Potassium Channels - antagonists & inhibitors</subject><subject>Ether-A-Go-Go Potassium Channels - metabolism</subject><subject>hERG ion channel</subject><subject>Humans</subject><subject>Kinetics</subject><subject>Mathematical models</subject><subject>Models, Cardiovascular</subject><subject>Models, Chemical</subject><subject>pro-arrhythmia</subject><subject>Protein Binding</subject><subject>QT prolongation</subject><subject>Therapeutic Equivalency</subject><subject>Torsades de Pointes</subject><subject>ventricular tachycardia</subject><issn>1045-3873</issn><issn>1540-8167</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kMtu1DAUhi0EohdY8ALIEisWae0kjh12nUuHoVWpZkCwsxznpPF0Eg-2ozbv0QfGMG13PZtzFt__H-lD6AMlJzTO6UbDCU1TUb5Ch5TlJBG04K_jTXKWZIJnB-jI-w0hNCsIe4sO0pxSwZg4RA_tfLXAy741lQnWeXxnQovXpjNb5fC1DdDrEU-GgGemacBBH_DE9LXpb_CF6SEY7fHM4isbIu0BhxbwWnWAr51VzrVjaDuj8cr42y942e22RqtgbO9xYx2eueEm4g2EEZ95D9538cM79KZRWw_vH_cx-nk-_zH9mlx-XyynZ5eJzikvk4w3BUBKOK8VsFrUVV1RxgrOeCWyUldEaSo0L1VZFXmj61wzrqCu8hwKrUl2jD7te3fO_hnAB7mxg-vjS0nzkqe8iJYi9XlPaWe9d9DInTOdcqOkRP7zL6N_-d9_ZD8-Ng5VB_Uz-SQ8Aqd74M5sYXy5SX6bzp8qk33C-AD3zwnlbmXBM87kr6uFLAShk9XviVxnfwHEip_8</recordid><startdate>201402</startdate><enddate>201402</enddate><creator>DI VEROLI, GIOVANNI Y.</creator><creator>DAVIES, MARK R.</creator><creator>ZHANG, HENGGUI</creator><creator>ABI-GERGES, NAJAH</creator><creator>BOYETT, MARK R.</creator><general>Blackwell Publishing Ltd</general><general>Wiley Subscription Services, Inc</general><scope>BSCLL</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>K9.</scope></search><sort><creationdate>201402</creationdate><title>hERG Inhibitors with Similar Potency But Different Binding Kinetics Do Not Pose the Same Proarrhythmic Risk: Implications for Drug Safety Assessment</title><author>DI VEROLI, GIOVANNI Y. ; 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 & 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 & 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 & Calcified Tissue Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><jtitle>Journal of cardiovascular electrophysiology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>DI VEROLI, GIOVANNI Y.</au><au>DAVIES, MARK R.</au><au>ZHANG, HENGGUI</au><au>ABI-GERGES, NAJAH</au><au>BOYETT, MARK R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>hERG Inhibitors with Similar Potency But Different Binding Kinetics Do Not Pose the Same Proarrhythmic Risk: Implications for Drug Safety Assessment</atitle><jtitle>Journal of cardiovascular electrophysiology</jtitle><addtitle>J Cardiovasc Electrophysiol</addtitle><date>2014-02</date><risdate>2014</risdate><volume>25</volume><issue>2</issue><spage>197</spage><epage>207</epage><pages>197-207</pages><issn>1045-3873</issn><eissn>1540-8167</eissn><abstract>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.</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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