A margin of 30- to 100-fold between hNav 1.5 IC50 and fCmax confers an acceptable degree of safety from QRS prolongation, which occurs at free plasma levels 15-fold below the IC50.
A safety margin of 30- to 100-fold between hNav1.5 IC50 and free Cmax is recommended to avoid drug-induced QRS prolongation in early drug discovery.
Absolute Event Rate: 67% vs 72%
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 IC(50) values) was measured in an automated electrophysiology-based assay. These IC(50) values were compared with published reports of the corresponding unbound (free) plasma concentrations attained during clinical use (fC(max)) to provide an IC(50) : fC(max) ratio. KEY RESULTS For 42 Class I anti-arrhythmics and other QRS prolonging drugs, 67% had IC(50) : fC(max) ratios 100. Finally, we determined the relationship between the IC(50) 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 IC(50) at hNa(v) 1.5 channels. CONCLUSIONS AND IMPLICATIONS: A margin of 30- to 100-fold between hNa(v) 1.5 IC(50) 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 IC(50) at hNa(v) 1.5 channels. LINKED ARTICLE: This article is commented on by Gintant et al., pp. 254-259 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476-5381.2011.01433.x.
Harmer et al. (Tue,) conducted a other in Drug-induced QRS prolongation (n=97). hNav 1.5 channel blocking drugs vs. Non-QRS prolonging drugs was evaluated on Proportion of drugs with specific IC50 : fCmax ratios (<30 for QRS prolonging, >100 for non-QRS prolonging). A margin of 30- to 100-fold between hNav 1.5 IC50 and fCmax confers an acceptable degree of safety from QRS prolongation, which occurs at free plasma levels 15-fold below the IC50.