Stem Cell-Derived Cardiomyocytes as a Tool for Studying Proarrhythmia: A Better Canary in the Coal Mine?
Does a new drug candidate carry risk for torsades de pointes?
Proarrhythmia is a leading cause of hospitalization for adverse drug events, and screening for proarrhythmic potential due to QT interval prolongation has become a major component of the development process for any new drug candidate. Conventional wisdom, now imbedded in regulatory guidelines from the Food and Drug Administration and other regulatory agencies, holds that drug block of the rapid component of the cardiac delayed-rectifier potassium current, IKr, is the major proximate mechanism underlying prolongation of cardiac action potentials, an effect that leads to early afterdepolarizations in vitro and is manifest on the surface ECG as QT prolongation and occasionally torsades de pointes.1, 2 As a result, regulatory guidance suggests an early look at IKr blocking potency of new drug entities, even recognizing that other mechanisms, some newly-described,3,4 may contribute.
- Received March 12, 2013.
- Accepted March 13, 2013.