Authors: Newbold, Paul; Sanders, Nick¹; Reele, Stots B.²

Source: British Journal of Clinical Pharmacology, Volume 63, Number 3, March 2007 , pp. 279-287(9)

Publisher: Wiley-Blackwell

Abstract:

What is already known about this subject

• When this study was conducted it was already known that the `standard' methods of correcting the QT interval for heart rate were not optimal and that bias could result in their use in certain circumstances, in particular when drugs or conditions also induced wide fluctuations in heart rate.

• The use of subject specific correction methods had been advocated and whilst these had been shown to apparently correct QT interval over usual physiological heart rates, they had not been tested under conditions where drugs could potentially increase heart rate and `standard' correction methods gave apparent increases in QT interval. Furthermore, subject specific correction methods had usually been generated over a normal physiological heart rate range and made the assumption that the relationship remained linear outside of this usual range. What this study adds

• A subject specific correction factor for QT correction can be calculated from a wide range of heart rates using exercise testing and the relationships between QT and RR are unique for a given individual.

• The generation of subject specific correction factors from ECGs collected under resting conditions is not a robust method.

• That subject specific correction factors derived from exercise testing are not appropriate to apply to drugs (with no evidence to suggest effects on the QT interval) that induce increases in heart rate and that the relationship between the QT and RR interval during exercise is clearly different to the QT/RR relationship of a drug that increases heart rate. Aims

We sought to investigate subject specific QT interval correction factors (SSCF) determined at rest and after exercise and to determine the validity of these factors after the administration of a probe drug known to increase heart rate without directly affecting cardiac repolarization. Methods

Thirty-two healthy volunteers underwent graded exercise, multiple recordings of electrocardiogram during rest over a day and a treatment phase administering inhaled placebo or sibenadet (a β₂-adrenoceptor/dopamine D₂-receptor agonist) at 250, 500 or one of 750 or 1000 µg. SSCF were determined from linear regression of plots of log RR interval vs. log QT after exercise (QTcX), rest (QTcR), and combined data (QTcC). The SSCFs along with Bazett & Fridericia corrections were applied to the ECGs after inhalation of sibenadet. Results

SSCFs obtained from the combination of the exercise and resting day (mean QTcC = 0.41) and exercise alone (mean QTcX = 0.40) were similar with a good fit to the data (mean r² = 0.92 and 0.93, respectively) while data at rest resulted in a less pronounced slope (mean QTcR = 0.27) and poorer fit (mean r² = 0.52). After the administration of sibenadet, none of the SSCFs, Bazett or Fridericia corrections adequately corrected QT for heart rate induced changes. Conclusions

Neither a SSCF from exercise, Bazett's or Fridericia's correction factors, adequately corrected the QT interval after the administration of a sympathomimetic agonist drug to increase heart rate in healthy volunteers demonstrating the potential need for QT/RR correction factors to be tailored for each drug studied.

Keywords: β-adrenoceptor agonist; exercise; heart rate; QT interval; sibenadet; subject specific correction factor

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1365-2125.2006.02763.x

Affiliations: 1: Clinical Science, AstraZeneca R & D Charnwood, Loughborough, Leicestershire LE11 5RH and 2: Clinical Pharmacology, AstraZeneca PO Box 15437, Wilmington, DE, 19850-5437, USA

Publication date: 2007-03-01

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