RT Journal Article SR Electronic T1 The Relationship of Clinical QT Prolongation to Outcome in the Conscious Dog Using a Beat-to-Beat QT-RR Interval Assessment JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 828 OP 833 DO 10.1124/jpet.102.035220 VO 302 IS 2 A1 Anthony A. Fossa A1 Michael J. DePasquale A1 David L. Raunig A1 Michael J. Avery A1 Derek J. Leishman YR 2002 UL http://jpet.aspetjournals.org/content/302/2/828.abstract AB QT interval prolongation of the electrocardiogram has been associated with the occurrence of life-threatening fatal ventricular arrhythmias. To understand the relationship between preclinical cardiac conduction assessment to clinical outcome, comparisons of free (unbound)-plasma drug concentrations and their associated effects in the conscious mongrel dog were made to the free plasma concentrations in humans reported to produce QT prolongation. E-4031 (an experimental class III antiarrhythmic), cisapride, terfenadine, terodiline, and verapamil all affect cardiac repolarization and can produce QT prolongation in humans. In the conscious dog, the QT interval was assessed on a beat-to-beat basis in relation to each preceding RR interval at concentrations approximating the same unbound human concentrations. E-4031, cisapride and terodiline statistically increased the QTRR1000 interval [the QT interval at a 60 beats/min (bpm) heart rate] 23, 8, and 9 ms, respectively, at concentrations 0.3 to 15.8 times their relevant clinical level. Increases were not observed for terfenadine or verapamil (p > 0.05 at all doses). Inspection of individual dog QT versus RR interval relationships showed clear QT interval responses specific to each treatment but not readily apparent when data are averaged at a heart rate of 60 bpm. For specific rectifier K+ current (IKr) blockers, robust effects on mean QT prolongation can be detected. However, for drugs that affect repolarization through multiple channels, the effect on the mean QT interval may be more difficult to detect. Inspection of the beat-to-beat QT-RR interval relationship in an individual animal can increase the sensitivity for more accurate clinical prediction. The American Society for Pharmacology and Experimental Therapeutics