hERG Inhibition Assay

Part of the core battery of Safety Pharmacology tests required for IND submission Whole-cell current amplitude and kinetics measurements verify the results of the interactions of a test article with the product of the hERG gene, a K+-selective ion channel responsible for the IKr repolarizing current. IKr current inhibition has been shown to prolong the cardiac action potential, a phenomenon associated with increased risk of arrhythmia. IKr current inhibition accounts for the vast majority of known cases of drug-induced QT- prolongation.

Method

Manual patch-clamp, whole-cell configuration.

• Number of cells exposed to the test article: 7 (screens: 3)
• Number of concentrations of test article: 4 (screens: 3)
• Method of test article exposure: cumulative concentrations in closed-circuit perfusion, or constant perfusion of individual concentrations
• Voltage pulse: partial current-voltage relationship
• A study includes positive and vehicle controls as well as a reference article

• A quantitative assessment of IKr current inhibition
• Determination of the IC50 value (if applicable)
• Analysis of both amplitude and current kinetics as indicators of inhibition
• FDA-ready hard copy and e-report for electronic IND submission
• Holistic interpretation of a positive signal, considering all other data generated

Pre-IND (GLP-compliant) or exploratory designs (screen = non-GLP compliant)