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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 that they could also initiate "torsades de pointe".
General non clinical testing B guidelines strategy
PhysioStim evaluates the cardiovascular safety of assay compounds compared to reference compounds in accordance with the CPMP Points to Consider document (CPMP 986/96; 1997) and ICHS7B guidelines (Step 4, May 2005).
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.
BUT
hERG assays could conceal “false positive” compounds :
hERG POSITIVE (hERG current inhibited) BUT no TdP reported.
Hence, in order to avoid false positive results, PhysioStim recommends to perform:
hERG ASSAYS + ADDITIONAL TESTS as action potential recordings, human NaV1.5 assays, human KVLQT1-MinK assays, human CaV1.2, Isolated Langendorff heart….