{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,4]],"date-time":"2026-03-04T04:20:05Z","timestamp":1772598005673,"version":"3.50.1"},"reference-count":32,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2013,10,7]],"date-time":"2013-10-07T00:00:00Z","timestamp":1381104000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"name":"AstraZeneca UK"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cardiovasc electrophysiol"],"published-print":{"date-parts":[[2014,2]]},"abstract":"<jats:title>Drug Mode of Action and hERG\u2010Related Safety<\/jats:title><jats:sec><jats:title>Introduction<\/jats:title><jats:p>Since the discovery of the link that exists between drug\u2010induced 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, IC<jats:sub>50<\/jats:sub> values are compared to projected plasma concentrations to define a safety margin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>We aimed to show that drugs with similar hERG potency are not uniformly pro\u2010arrhythmic\u2014this depends on the drug binding kinetics and mode of action (trapped or not) rather than the IC<jats:sub>50<\/jats:sub> value only. We used a mathematical model of hERG and its related encoded current I<jats:sub>Kr<\/jats:sub> 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\u2010ECG (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 IC<jats:sub>50<\/jats:sub> whereas maximal pro\u2010arrhythmic risk was observed for trapped drugs at the same concentration (QT interval prolongation, 23.1%).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>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.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jce.12289","type":"journal-article","created":{"date-parts":[[2013,9,12]],"date-time":"2013-09-12T15:02:37Z","timestamp":1378998157000},"page":"197-207","source":"Crossref","is-referenced-by-count":66,"title":["hERG Inhibitors with Similar Potency But Different Binding Kinetics Do Not Pose the Same Proarrhythmic Risk: Implications for Drug Safety Assessment"],"prefix":"10.1111","volume":"25","author":[{"given":"GIOVANNI Y.","family":"DI VEROLI","sequence":"first","affiliation":[{"name":"Institute of Cardiovascular Sciences University of Manchester  Manchester UK"},{"name":"Translational Safety Drug Safety &amp; Metabolism  AstraZeneca Manchester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"MARK R.","family":"DAVIES","sequence":"additional","affiliation":[{"name":"Clinical Informatics R&amp;D Information  AstraZeneca Manchester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"HENGGUI","family":"ZHANG","sequence":"additional","affiliation":[{"name":"Biological Physics University of Manchester  Manchester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"NAJAH","family":"ABI\u2010GERGES","sequence":"additional","affiliation":[{"name":"Translational Safety Drug Safety &amp; Metabolism  AstraZeneca Manchester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"MARK R.","family":"BOYETT","sequence":"additional","affiliation":[{"name":"Institute of Cardiovascular Sciences University of Manchester  Manchester UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2013,10,7]]},"reference":[{"key":"e_1_2_6_2_1","doi-asserted-by":"publisher","DOI":"10.2165\/00002018-200124050-00001"},{"key":"e_1_2_6_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9149(94)90006-X"},{"key":"e_1_2_6_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1572-0241.2001.03927.x"},{"key":"e_1_2_6_5_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1476-5381.2009.00547.x"},{"key":"e_1_2_6_6_1","doi-asserted-by":"publisher","DOI":"10.1021\/tx800035b"},{"key":"e_1_2_6_7_1","first-page":"3","volume-title":"Note for Guidance on the Nonclinical Evaluation of the Potential for Delayed Ventricular Repolarization (QT Interval Prolongation) by Human Pharmaceuticals","author":"ICH S7B","year":"2005"},{"key":"e_1_2_6_8_1","first-page":"1","volume-title":"Note for Guidance on the Clinical Evaluation of QT\/QTc Interval Prolongation and Proarrhythmic Potential for Non\u2010Antiarrhythmic Drugs","author":"ICH E14","year":"2005"},{"key":"e_1_2_6_9_1","doi-asserted-by":"publisher","DOI":"10.1046\/j.1540-8167.2004.04099.x"},{"key":"e_1_2_6_10_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10565-006-0141-x"},{"key":"e_1_2_6_11_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2011.00073"},{"key":"e_1_2_6_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(02)00846-5"},{"key":"e_1_2_6_13_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-200403000-00007"},{"key":"e_1_2_6_14_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00808.2011"},{"key":"e_1_2_6_15_1","doi-asserted-by":"publisher","DOI":"10.1093\/cvr\/cvr044"},{"key":"e_1_2_6_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.vascn.2010.02.007"},{"key":"e_1_2_6_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0707356"},{"key":"e_1_2_6_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0079-6107(98)00002-9"},{"key":"e_1_2_6_19_1","volume-title":"Ion Channels of Excitable Membranes","author":"Hille B","year":"2001"},{"key":"e_1_2_6_20_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.00511.2012"},{"key":"e_1_2_6_21_1","doi-asserted-by":"publisher","DOI":"10.1063\/1.4822377"},{"key":"e_1_2_6_22_1","doi-asserted-by":"publisher","DOI":"10.1152\/ajpheart.01216.2008"},{"key":"e_1_2_6_23_1","first-page":"351","article-title":"Characteristics of the delayed rectifier current (IKr and I Ks) in canine ventricular epicardial, midmyocardial, and endocardial myocytes","volume":"76","author":"Liu DW","year":"1995","journal-title":"A weaker I Ks contributes to the longer action potential of the M cell. 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