logo linkedin

Objec­tives

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.

Although…

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 :

hERG ASSAYS
+
ADDI­TIONAL TESTS

(action poten­tial record­ings, ion chan­nel assays, iso­lated Lan­gen­dorff per­fused heart….)