Expert hERG assays for preclinical safety studies
ICH level: Mandatory study according to ICH S7B
Why conduct a hERG assay?
hERG assays are essential when it comes to studying the cardiovascular safety of a new drug or compound. hERG stands for the human Ether-a-go-go-Related Gene, a gene that codes for a protein known as Kv11.1. It’s the pore forming subunit of a potassium ion channel that conducts the rapid component of the delayed rectifier potassium current known as IKr. This ion channel contributes to the electrical activity of the heart and coordinates heart beatings. When the hERG channel cannot adequately conduct electrical current across the cell membrane, this can result in a potentially fatal disorder called long QT syndrome (LQT2).
hERG assays & preclinical safety studies
Preclinical hERG assays aim to identify potential inhibitory effects early in drug discovery. Current ICH Guidelines state that hERG assays are mandatory, as a number of clinically successful drugs have had the tendency to inhibit hERG and create a concomitant risk of sudden death. As a result, a large number of drugs have been withdrawn from the market or during late stage clinical trials due to cardiotoxic effects.
What hERG assays measure
Inhibition of the hERG channel by pharmaceutical substances is the primary cause of drug-induced QT prolongation. IKr current inhibition has been shown to prolong the cardiac action potential duration, a phenomenon associated with increased risk of QT interval prolongation. This can lead to potentially fatal ventricular tachyarrhythmia, known as Torsades de pointe.
- Patch Clamp
- 3 or 4 increasing cumulative concentrations of assay compound
- Experiment conducted at room temperature or at physiological temperature (35°C)
- Human Embryonic Kidney HEK-293 cells
- 6 treated cells and 6 control cells (as basic design protocol but can be adapted)
- Amplitude of the tail current upon repolarization to –40 mV (pA)
- Amplitude of the base current at –80 mV (pA)
- Inhibition of hERG tail current amplitude (%)
Typical concentration-dependent effects of cisapride on IKr currents recorded from HEK-293 cells
- ion current inhibition measurement
- IC50 value
Reference compounds or positive controls
|REFERENCE COMPOUNDS hERG||IC50|
|E– 4031||32.3 nM|
Advice from our expert scientists
hERG assays may reveal “false positive” compounds such as Verapamil, which is hERG positive even though no Torsade de pointe is reported during clinic investigations. In order to avoid false positive results, PhysioStim recommends completing your hERG assay with additional tests: