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

Abstract

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 <30. For 55 non-QRS prolonging drugs tested, 72% had 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.

Figure 1

IC₅₀ : fC_max ratio calculations for verapamil and propafenone. (A) Typical hNa_v1.5 current recordings generated using an IonWorks™-based assay. Each individual recording shows data from a single well in response to vehicle (0.33% dimethyl sulphoxide, solid line) followed by a single concentration of verapamil (dotted line). Each recording is taken from the eighth pulse to 0 mV from a holding potential of −90 mV. (B) Graphs show concentration–effect curves for hNa_v1.5 channels generated using the same assay. The half maximal inhibitory concentration (IC₅₀) and maximal free plasma concentration in human (fC_max) values are also plotted. For propafenone, the hNa_v1.5 IC₅₀ is 1.2 µM and fC_max is 0.9 µM, giving a ratio (safety margin) of 1.3. For verapamil, the hNa_v1.5 IC₅₀ is 9.3 µM and the fC_max is 0.08 µM, giving a ratio of 115.

Figure 2

Log₁₀ of the IC₅₀ : fC_max ratios. IC₅₀ values at hNa_v1.5 channels were generated using a IonWorks™-based assay. The fC_max values are derived from published values of the maximum plasma concentration achieved in a clinical setting and the plasma protein binding value in humans. The vertical grey box indicates where ratios between 30 and 100 would fall. For source data, refer to Tables 1–3.

Figure 3

Analysis of fC_max, hNa_v1.5 IC₅₀ and derived ratios. (A) Distribution curves for fC_max and IC₅₀ values for the drugs analysed in this study. The distribution means [expressed as log₁₀ of (drug) ] were −6.6 ± 0.1 (R² = 0.95) for fC_max data and −4.5 ± 0.03 (R² = 0.99) for the IC₅₀ data. (B) Analysis of false positive (false +ve) and false negative (false −ve) rates versus IC₅₀ : fC_max ratios. Class I anti-arrhythmics (Na⁺ channel blockers) and other known QRS-prolonging drugs were classified as positive, and drugs not known to prolong QRS were classified as negative. The false positive/negative incidence was calculated for ratios using total and unbound (free) C_max values. A ratio of 30−100 has the optimal false positive/negative incidence for free drug concentration, as indicated by the dotted line.

Figure 4

Log₁₀ of (hNa_v1.5 IC₅₀ : [QRS]free), shown as therapeutic window. IC₅₀ data were generated using the IonWorks™-based assay. [QRS]free is the published value of mean lowest free plasma concentration associated with prolongation of the QRS complex in humans. For source data, refer to Tables 1 and 2.