Lack of correlation between exercise and sibenadet-induced changes in heart rate corrected measurement of the QT interval.
OBJECTIVE
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 beta(2)-adrenoceptor/dopamine D(2)-receptor agonist) at 250, 500 or one of 750 or 1000 microg. 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 r(2) = 0.92 and 0.93, respectively) while data at rest resulted in a less pronounced slope (mean QTcR = 0.27) and poorer fit (mean r(2) = 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.
Newbold
Paul
P
Discovery Medicine, AstraZeneca R & D Charnwood, Loughborough, Leicestershire LE11 5RH, UK. paul.newbold@astrazeneca.com
Sanders
Nick
N
Reele
Stots B
SB
D000328:Adult; D004305:Dose-Response Relationship, Drug; D015444:Exercise; D005260:Female; D006339:Heart Rate / Q000187:drug effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D013844:Thiazoles / Q000008:administration & dosage*
D013844:Thiazoles; C116267:sibenadet