title: Drug-induced QTC 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 IKr and INa exceed 200 nM.
  
  
  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 QTc prolongation in patients and Food and Drug Administration records suggest that incidence of ventricular tachycardia/ventricular fibrillation exceeds Torsade de Pointes.
  
  
  CONCLUSIONS
  For terfenadine, TRIaD predicts drug-induced proarrhythmia: with λ prolongation, Torsade de Pointes is preferred, otherwise ventricular tachycardia/ventricular fibrillation. APD/QTc alone is clearly inadequate for proarrhythmia evaluation.
authors.affiliation: Department of Pharmacology, KU Leuven, Leuven, Belgium. Luc.Hondeghem@ScreenQT.com
authors.forename: Luc M
authors.initials: LM
authors.lastname: Hondeghem
authors.forename: Karl
authors.initials: K
authors.lastname: Dujardin
authors.forename: Peter
authors.initials: P
authors.lastname: Hoffmann
authors.forename: Berengere
authors.initials: B
authors.lastname: Dumotier
authors.forename: Fred
authors.initials: F
authors.lastname: De Clerck
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography; D005260:Female; D006321:Heart / Q000187:drug effects*; D039563:Histamine H1 Antagonists, Non-Sedating / Q000009:adverse effects*; D006801:Humans; D066298:In Vitro Techniques; D008133:Long QT Syndrome / Q000139:chemically induced* / Q000150:complications; D010477:Perfusion; D011817:Rabbits; D017180:Tachycardia, Ventricular / Q000139:chemically induced* / Q000209:etiology; D016593:Terfenadine / Q000009:adverse effects*; D013997:Time Factors; D016171:Torsades de Pointes / Q000139:chemically induced / Q000209:etiology; D014693:Ventricular Fibrillation / Q000139:chemically induced / Q000209:etiology
chemical_list: D039563:Histamine H1 Antagonists, Non-Sedating; D016593:Terfenadine