Pearlstein Robert A, MacCannell K Andrew, Erdemli Gül, Yeola Sarita, Helmlinger Gabriel, Hu Qi-Ying, Farid Ramy, Egan William, Whitebread Steven, Springer Clayton, Beck Jeremy, Wang Hao-Ran, Maciejewski Mateusz, Urban Laszlo, Duca José S
Novartis Institutes for Bio- Medical Research, Inc., 100 Technology Square, Cambridge, MA 02139, USA.
Curr Top Med Chem. 2016;16(16):1792-818. doi: 10.2174/1568026616666160315142156.
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.
阻断人乙醚相关基因（hERG）钾通道可延长心室动作电位（AP）和QT间期，并引发早期后去极化（EADs）和尖端扭转型室性心动过速（TdP）心律失常。关于hERG阻断与TdP之间的因果关系、其他促成因素的相对权重、临床前促心律失常的确切指标以及人类真正的安全边际，存在不同观点。在此，我们使用计算机模拟技术来表征通道门控和结合动力学对hERG占有率的影响，以及阻断对人心室AP的影响。对于在空间上与关闭通道兼容（被困于失活通道）的化合物与那些与关闭/关闭状态不兼容并在失活期间被排出的化合物，门控效应有所不同。可捕获阻滞剂的占有率达到平衡水平，而非可捕获阻滞剂的占有率在每个AP周期中建立并衰减。在我们的AP模拟中，开放/失活通道占有率约为83%（不可捕获）与约63%（可捕获）时会引发EADs。总体而言，我们得出结论，对于不可捕获的阻滞剂，在治疗暴露水平下的hERG占有率可能是可耐受的，但对于能够达到促心律失常占有率水平的可捕获阻滞剂则不然。此外，广泛使用的雷德芬安全指数可能偏向于可捕获阻滞剂，高估了不可捕获情况下暴露-半数抑制浓度（IC50）的分离度。
