On the relationship between block of the cardiac Na+ channel and drug-induced prolongation of the QRS complex

BACKGROUND AND PURPOSE Inhibition of the human cardiac Na+ channel (hNa(v)1.5) can prolong the QRS complex and has been associated with increased mortality in patients with underlying cardiovascular disease. The safety implications of blocking hNa(v)1.5 channels suggest the need to test for this activity early in drug discovery in order to design out any potential liability. However, interpretation of hNa(v)1.5 blocking potency requires knowledge of how hNa(v)1.5 block translates into prolongation of the QRS complex. EXPERIMENTAL APPROACH We tested Class I anti-arrhythmics, other known QRS prolonging drugs and drugs not reported to prolong the QRS complex. Their block of hNa(v)1.5 channels (as IC50 values) was measured in an automated electrophysiology-based assay. These IC50 values were compared with published reports of the corresponding unbound (free) plasma concentrations attained during clinical use (fC(max)) to provide an IC50 : fC(max) ratio. KEY RESULTS For 42 Class I anti-arrhythmics and other QRS prolonging drugs, 67% had IC50 : fC(max) ratios <30. For 55 non-QRS prolonging drugs tested, 72% had ratios >100. Finally, we determined the relationship between the IC50 value and the free drug concentration associated with prolongation of the QRS complex in humans. For 37 drugs, QRS complex prolongation was observed at free plasma concentrations that were about 15-fold lower than the corresponding IC50 at hNa(v)1.5 channels. CONCLUSIONS AND IMPLICATIONS A margin of 30- to 100-fold between hNa(v)1.5 IC50 and fC(max) appears to confer an acceptable degree of safety from QRS prolongation. QRS prolongation occurs on average at free plasma levels 15-fold below the IC50 at hNa(v)1.5 channels.