title: hERG inhibitors with similar potency but different binding kinetics do not pose the same proarrhythmic risk: implications for drug safety assessment.
abstract: BACKGROUND
  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.
  
  
  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%).
  
  
  CONCLUSIONS
  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.
authors.affiliation: Institute of Cardiovascular Sciences, University of Manchester, Manchester, UK; Translational Safety, Drug Safety & Metabolism, AstraZeneca, Manchester, UK.
authors.forename: Giovanni Y
authors.initials: GY
authors.lastname: DI Veroli
authors.forename: Mark R
authors.initials: MR
authors.lastname: Davies
authors.forename: Henggui
authors.initials: H
authors.lastname: Zhang
authors.forename: Najah
authors.initials: N
authors.lastname: Abi-Gerges
authors.forename: Mark R
authors.initials: MR
authors.lastname: Boyett
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000139:chemically induced* / Q000378:metabolism*; D001665:Binding Sites; D002121:Calcium Channel Blockers / Q000008:administration & dosage* / Q000009:adverse effects*; D003198:Computer Simulation; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008955:Models, Cardiovascular; D008956:Models, Chemical; D011485:Protein Binding; D013810:Therapeutic Equivalency
chemical_list: D002121:Calcium Channel Blockers; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; C000606913:KCNH2 protein, human
keywords: QT prolongation; Torsades de Pointes; computational modeling; drug binding kinetics; hERG ion channel; pro-arrhythmia; ventricular tachycardia