Screening for Acute I _Kr Block Is Insufficient to Detect Torsades de Pointes Liability

Abstract

Background New drugs are routinely screened for acute IKr blocking properties thought to predict QT prolonging and arrhythmogenic liability. However, recent data suggest that chronic (hours) drug exposure to PI3 kinase (PI3K) inhibitors used in cancer can prolong QT by inhibiting potassium currents and increasing late sodium current (INa-L) in cardiomyocytes. We tested the extent to which IKr blockers with known QT liability generate arrhythmias through this pathway. Methods and Results Acute exposure to dofetilide, an IKr blocker without other recognized electropharmacologic actions, produced no change in ion currents or action potentials in adult mouse cardiomyocytes, which lack IKr. By contrast, 2–48 hours’ exposure to the drug generated arrhythmogenic afterdepolarizations and up to 15-fold increases in INa-L. Including PIP3, a downstream effector for the PI3K pathway, in the pipette inhibited these effects. INa-L was also increased, and inhibitable by PIP3, with hours of dofetilide exposure in human iPSC-derived cardiomyocytes and in CHO cells transfected with SCN5A, encoding INa. Cardiomyocytes from dofetilide-treated mice similarly demonstrated increased INa-L and afterdepolarizations. Other agents with variable IKr blocking potencies and arrhythmia liability produced a range of effects on INa-L, from marked increases (E-4031, d-sotalol, thioridazine, erythromycin) to little or no effect (haloperidol, moxifloxacin, verapamil). Conclusions Some but not all drugs designated as arrhythmogenic IKr blockers can generate arrhythmias by augmenting INa-L through the PI3K pathway. These data identify a potential mechanism for individual susceptibility to proarrhythmia and highlight the need for a new paradigm to screen drugs for QT prolonging and arrhythmogenic liability.

Rat engineered heart tissue: a novel tool in the safety pharmacology toolkit?

“…-transient decay and relaxation time (T2; measured from peak contraction to 20 % relaxation). On the other hand, inhibition of I Kr (with E-4031) or I Ks (with HMR1556) did not affect T2 duration in EHTs, in agreement with the unaltered APD reported in other studies [22]. In contrast, combined inhibition of I Kr and I Ks did produce a significant prolongation in relaxation time in rat EHTs.…”

“…For example, EHTs allow analysis of both acute and long-term/chronic applications of a compound. Recent work by Yang et al [22] has shown that several substances that were considered specific I Kr blockers can additionally cause an increase in late Na ? -current (I NaL ) when applied chronically and that this may contribute to their torsadogenic potential.…”

Potassium Channel Blockade Enhances Atrial Fibrillation–Selective Antiarrhythmic Effects of Optimized State-Dependent Sodium Channel Blockade

“…44 This off-class effect was not explicitly investigated in our experiments. Nevertheless, combining dofetilide with a NCB would antagonize the proarrhythmic effect of I Na,L , potentially providing further antiarrhythmic action to this Na + /K + -channel combined block.…”

Safety of Oral Dofetilide for Rhythm Control of Atrial Fibrillation and Atrial Flutter

“…It is a Vaughan Williams class III antiarrhythmic that causes a dose-dependent increase in both the atrial and ventricular refractory periods by selectively blocking the rapid component of the delayed rectifier potassium channel (I kr ) and increasing late sodium current (I Na-L ) in cardiac cells, thus prolonging the action potential in cardiac myocytes. 1 The Food and Drug Administration (FDA) first approved it in 1999 for converting to and maintaining sinus rhythm in patients with highly symptomatic AF and flutter of more than 1-week duration who were capable of being cardioverted. Although it is generally well tolerated with few clinical side effects, dofetilide requires inpatient initiation because of the known finite risk of Torsade de pointes (TdP).…”