What makes safety studies so essential ?
Apart from some cardiovascular drugs, well-known for their proarrhythmogenic activity in certain circumstances, there are a number of other therapeutic classes of compounds which have been the cause behind serious and potentially fatal proarrhythmias. These include, amongst others, antipsychotics, antihistamines, diuretics, gastrointestinal prokinetics, antidepressants, anticonvulsants, antibiotics, antimalarials, antimycotics, antiasthmatics, anticancer drugs… Medicinal products that prolong cardiac repolarisation have been associated with a specific, potentially fatal polymorphic ventricular tachycardia termed “Torsades de pointe” (TdP). Moreover, several animal studies have shown that an increasing number of non-cardiovascular target molecules causes potential risk for QT interval prolongation, and therefore may induce “torsades de pointe”.
General non clinical testing ICH S7B guidelines strategy
PhysioStim evaluates the cardiovascular safety of assay compounds compared to reference compounds in accordance with the ICH S7B guidelines. These documents recommend greater focus on both the in vitro measurement of the cardiac action potentials (using the intracellular microelectrode technique), ionic currents (using the patch-clamp technique) and the in vivo assessment of effects induced by the prolongation of the QT interval.
Why hERG channel ?
Almost all drugs reported to exert adverse cardiac effects (QT prolongation, torsades de pointe) in humans have been found to block hERG → the potency of hERG inhibition should be taken into account in integrated risk assessment.
hERG assays could conceal “false positive” compounds such as Verapamil which is hERG POSITIVE BUT no TdP were reported in clinic.
Hence, in order to avoid false positive results, PhysioStim recommends to perform :