New cell models and assays in cardiac safety profiling

Area of Science:

• Cardiovascular Pharmacology
• Drug Safety Evaluation
• Electrophysiology

Background:

• Drug-induced QT interval prolongation is associated with life-threatening ventricular arrhythmias like Torsades de Pointes.
• Blockade of the human ether-à-go-go-related gene (hERG) potassium channel is a primary mechanism underlying QT prolongation.
• Comprehensive in vitro and preclinical in vivo testing is crucial for new drug entities to mitigate cardiac risks.

Purpose of the Study:

• To review established and innovative assay systems for assessing drug-induced cardiac repolarization disturbances.
• To discuss the role of hERG channel assays and direct ventricular repolarization studies.
• To explore the potential of novel biological models in cardiac safety pharmacology.

Main Methods:

• Analysis of drug action on hERG channel function using established in vitro test systems.
• Direct assessment of ventricular repolarization using cardiac tissue preparations.
• Discussion of emerging assays utilizing stem-cell-derived cardiomyocytes and cardiac tissue slices.

Main Results:

• Established in vitro assays primarily focus on hERG channel blockade.
• More advanced assays directly measure ventricular repolarization in cardiac tissue.
• Novel models like stem-cell-derived cardiomyocytes offer future potential for innovative assay design.

Conclusions:

• Rigorous evaluation of drug effects on cardiac repolarization is essential for patient safety.
• A combination of established and novel assay systems is necessary for comprehensive cardiac safety assessment.
• Future developments in biological models promise enhanced capabilities for cardiac safety pharmacology.