Drug-Induced QT_C Prolongation Dangerously Underestimates Proarrhythmic Potential: Lessons From Terfenadine

Abstract

Background: 

Terfenadine's proarrhythmia prompted market withdrawal; therapeutic antihistaminic concentration is less than 1 nM, whereas IC₅₀ of I_Kr and I_Na exceed 200 nM.

Methods and Results: 

Rabbit hearts were perfused with terfenadine (1-10,000 nM; 10-450 minutes). A dosage of 1 nM tended to shorten action potential duration (APD₆₀) (-30 ± 30.5 ms; n = 6); 10 nM (450 minutes) significantly prolonged APD₆₀ (46 ± 11 ms; n = 6), but after 1 hour washout, APD₆₀ further prolonged. Above 30 nM, APD₆₀ shortening was followed by prolongation; net effect depended on exposure time (n = 33). In the μM range, cardiac wavelength (λ) shortened (APD₆₀ shortened, conduction slowed; P < 0.05). Terfenadine induced triangulation, reverse use dependence, instability and dispersion of repolarization (TRIaD) at 1 to 1000 nM, increasing with concentration (450 minutes: 1 nM yielded 50% of hearts, 10 nM 100%) and exposure (100 nM: 10 minutes yielded 16%, 30 minutes 33%, 150 minutes 66%, 450 minutes 100%). TRIaD with APD prolongation preceded two Torsade de Pointes, with shortening seven ventricular tachycardia and five ventricular fibrillation. Terfenadine causes normally little QT_c prolongation in patients and Food and Drug Administration records suggest that incidence of ventricular tachycardia/ventricular fibrillation exceeds Torsade de Pointes.

Conclusion: 

For terfenadine, TRIaD predicts drug-induced proarrhythmia: with λ prolongation, Torsade de Pointes is preferred, otherwise ventricular tachycardia/ventricular fibrillation. APD/QT_c alone is clearly inadequate for proarrhythmia evaluation.