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hERG Inhibitors with Similar Potency But Different Binding Kinetics Do Not Pose the Same Proarrhythmic Risk: Implications for Drug Safety Assessment
Author(s) -
VEROLI GIOVANNI Y.,
DAVIES MARK R.,
ZHANG HENGGUI,
ABIGERGES NAJAH,
BOYETT MARK R.
Publication year - 2014
Publication title -
journal of cardiovascular electrophysiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.193
H-Index - 138
eISSN - 1540-8167
pISSN - 1045-3873
DOI - 10.1111/jce.12289
Subject(s) - herg , qt interval , pharmacology , potency , drug , medicine , long qt syndrome , prolongation , drug action , cardiac action potential , ventricular action potential , torsades de pointes , drug discovery , repolarization , chemistry , electrophysiology , in vitro , potassium channel , biochemistry
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, IC 50 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 IC 50 value only. We used a mathematical model of hERG and its related encoded current I Kr 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 IC 50 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.