Preclinical Drug Safety and Cardiac Ion Channel Screening

Abstract

A new chemical entity must demonstrate efficacy and safety in order to be considered a successful therapeutic agent. Towards that goal, it is best to discover drugs demonstrating a wide concentration range between (lower) preclinical efficacious plasma concentrations and (higher) plasma concentrations eliciting preclinical off-target adverse effects. Drugs possessing such characteristics provide greater flexibility in clinical trials and explorations into alternative indications. Thus, preclinical studies related to both efficacy and safety must be considered equally important during drug discovery efforts. Cardiac safety plays a key role in defining the safety of novel therapeutics, and defining a drug's therapeutic window/safety margin.Much emphasis has been placed in the past decade on detecting (and avoiding) the ability of non-cardiovascular drugs to delay or alter ventricular repolarization (acquired long QT syndrome [1]). This focus arises in part from the association of delayed repolarization to the rare but potentially life-threatening arrhythmia torsades de pointes. As torsades is a rare event, surrogate markers are employed to detect and avoid this potential proarrhythmic risk. Preclinically, the most recognized in vitro marker for delayed repolarization is drug block of I Kr (an outward repolarizing current that initiates and defines terminal ventricular repolarization). In humans, the a-subunit of the I Kr channel is encoded by the human ether-a-go-go related gene (hERG) gene. Block of hERG/I Kr along with prolongation of the QT interval (an interval on the ECG that generally represents the onset of ventricular depolarization and the termination of ventricular repolarization) form the presentday cornerstone for cardiac electrophysiologic safety testing. Due to the importance of testing hERG current as a surrogate marker of proarrhythmia, great strides have been made in developing and streamlining testing protocols/procedures to evaluate