Title:Implications of Dynamic Occupancy, Binding Kinetics, and Channel Gating Kinetics for hERG Blocker Safety Assessment and Mitigation
VOLUME: 16 ISSUE: 16
Author(s):Robert A. Pearlstein, K. Andrew MacCannell, Gül Erdemli, Sarita Yeola, Gabriel Helmlinger, Qi-Ying Hu, Ramy Farid, William Egan, Steven Whitebread, Clayton Springer, Jeremy Beck, Hao-Ran Wang, Mateusz Maciejewski, Laszlo Urban and José S. Duca
Affiliation:Novartis Institutes for Bio- Medical Research, Inc., 100 Technology Square, Cambridge, MA 02139, USA.
Keywords:Potassium channel, WaterMap, Binding kinetics, Bisaryl, Trapping, Mitigation.
Abstract:Blockade of the hERG potassium channel prolongs the ventricular action potential (AP) and QT interval, and
triggers early after depolarizations (EADs) and torsade de pointes (TdP) arrhythmia. Opinions differ as to the causal relationship
between hERG blockade and TdP, the relative weighting of other contributing factors, definitive metrics of preclinical
proarrhythmicity, and the true safety margin in humans. Here, we have used in silico techniques to characterize
the effects of channel gating and binding kinetics on hERG occupancy, and of blockade on the human ventricular AP.
Gating effects differ for compounds that are sterically compatible with closed channels (becoming trapped in deactivated
channels) versus those that are incompatible with the closed/closing state, and expelled during deactivation. Occupancies
of trappable blockers build to equilibrium levels, whereas those of non-trappable blockers build and decay during each AP
cycle. Occupancies of ~83% (non-trappable) versus ~63% (trappable) of open/inactive channels caused EADs in our AP
simulations. Overall, we conclude that hERG occupancy at therapeutic exposure levels may be tolerated for nontrappable,
but not trappable blockers capable of building to the proarrhythmic occupancy level. Furthermore, the widely
used Redfern safety index may be biased toward trappable blockers, overestimating the exposure-IC50 separation in nontrappable
cases.
