The Relationship of Clinical QT Prolongation to Outcome in the Conscious Dog Using a Beat-to-Beat QT-RR Interval Assessment

Abstract

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 QT RR1000 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 Ͼ 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 ϩ 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clinical prediction.In the past four years, several drugs such as sertindole, cisapride, and terfenadine have been withdrawn from the marketplace due to the rare occurrence of the fatal ventricular arrhythmia, Torsades de Pointes (TdP). Retrospective evaluation of the European database on these compounds indicated an association of QT prolongation in patients on these medications (Haverkamp et al., 2000). As a result, the Committee for Proprietary Medicinal Products (1997) issued a Points to Consider document on the conduct of studies for the development of noncardiovascular drugs. This and further impending guidance from the International Committee for Harmonization have focused a great deal of attention on the preclinical assessments used to predict the liability for patient populations to experience QT prolongation. Despite the ongoing controversy concerning whether there is a definitive cause and effect relationship, QT prolongation has by default become a surrogate marker for risk of developing TdP.This study is one of a series of assessments from our laboratories examining the utility of a variety of both in vitro and in vivo preclinical assessments of drugs that are known to produce clinically detectable QT prolongation in humans. Although the magnitude of the QT interval prolongation and the risk associated with TdP are s...

The electrocardiogram of the Beagle dog: reference values and effect of sex, genetic strain, body position and heart rate

“…This question has been extensively assessed and different formulas have been proposed to correct QT values for HR in man, the best known being the formulas of Bazett (1920) and of Fridericia (1920). However, these formulas established in humans are not necessarily valid for dogs and a number of authors have proposed specific methods of correction or formulas for dogs (Van de Water et al 1989, Todt et al 1992, Matsunaga et al 1997, Spence et al 1998, Raunig et al 2001, Fossa et al 2002. In a previous publication, we have shown that none of these formulas perfectly correct the QT interval of dogs in our laboratory.…”

The Dog's Role in the Preclinical Assessment of QT Interval Prolongation

“…In recent years, investigators have developed other formulae to adjust the QT interval, including those involving linear regression and analysis of covariance equations (2,6,15,56,63,64). Recent reports propose that QT "correction" itself may be inappropriate and the investigators involved with these studies suggest alternate solutions (19). In the current environment, it is probably prudent to report the corrected QT interval as a well-characterized point of reference with recognition that in a few years the QTc may be of little scientific value as our understanding of this relationship develops.…”

“…Numerous correction formulae have been developed to adjust for the inverse relationship between heart rate and QT interval, although the shortcomings of these mathematical interpolations are many. Many methods of correction, and indeed noncorrection, have been proposed (2,6,15,19,56,63,64). Although the use of conscious sling-trained dogs can reduce the variability observed in the restrained animal, it is still considered preferable to utilize telemetry implants that derive cardiovascular parameters from the conscious, freeroaming animal.…”

Tomenendalova J: How to approach the QT interval in dogs - the state of the heart: a review

“…This approach is highly valid because it accounts for QT variation with HR but does not assume a mathematical relationship, thus making no assumptions about the nature of the QT-HR relationship. This approach, however, requires many data points, either acquired from many, or from one individual (Davey, 2002;Fossa et al, 2002). A continuous evaluation of QT can be accomplished with a better-fitting mathematical model than the single-coefficient model.…”