Abstract
In toxicity studies, the ECG is recorded over a range of escalating doses and the assessment of QT prolongation is made by comparing treated to untreated animals. As the QT interval and heart rate are inversely related, any imbalance in the distribution of heart rate across groups may bias this comparison. To avoid that risk, a formula for correcting QT intervals for heart rate is derived from the fit of a power model with random coefficients to historical controls. The correction [QTc = QT/sqrt[5]RR]% and heart rate-specific reference ranges for QT are then used to refine the toxicity evaluation. The factor for dogs (1/5) is smaller than those used in humans (Bazett: 1/2; Fridericia: 1/3). This suggests that species-specific correction factors should be used to avoid misleading conclusions on QT prolongation.
This is a preview of subscription content, access via your institution.
References
- 1.
Moss A. Measurement of the Q. interval and the risk associated with QT. interval prolongation: A review. Am J Cardiol 1993;72:23B–25B.
- 2.
European Medicines Evaluation Agency. Human Medicines Evaluation Unit. Points to consider: The assessment of the potential for Q. interval prolongation by non-cardiovascular medicinal products. Committee for Proprietary Medicinal Products/986/96, 1997.
- 3.
Ahnve S. Correction of the Q. interval for heart rate: review of different formulas and the use of Bazett’s formula in myocardial infarction. Am Heart J. 1985;568–574.
- 4.
Funck-Brentano C, Jaillon P. Rate-corrected QT interval: techniques and limitations. Am J Cardiol 1993;72:17B–22B.
- 5.
Bazett HC. An analysis of the time relationship of electrocardiograms. Heart 1920;7:353–380.
- 6.
Fridericia LS. Die systolendauer im elektrokardiogramm bei normalen menchen und bei herzkranken. Acta Med Scand 1920;53:469.
- 7.
Mann WA, Kerns WD, Kinter LB. Normalization of Q. interval (QTc) in canine electrocardiography. Soc Toxicol Ann Mtg Proc 1994;14(1):376.
- 8.
Matsunaga T, Mitsui T, Harada T, Murano H, Shibu-tani Y. QT corrected for heart rate and relation between QT and RR intervals in beagle dogs. J Pharmacolog Toxicol Methods 1998;38:201–209.
- 9.
Gough K, Hutchison M, Keene O, Byrom B, Ellis S, Lacey L, McKellar J. Assessment of dose proportionality: report from the Statisticians in the Pharmaceutical Industry/Pharmacokinetics UK Joint Working Party. Drug Inf J 1995;29:1039–1048.
- 10.
Rutter C, Elashoff R. Analysis of longitudinal data: random coefficient regression modeling. Stat Med 1994;13:1211–1231.
- 11.
Little R, Milliken G, Stroup W, Wolfinger, R. SAS System for Mixed Models. Cary, NC: SAS Institute Inc.; 1996:253–266.
- 12.
Royston P. Constructing time-specific reference ranges. Stat Med 1991;10:675–690.
- 13.
Tukey JW, Ciminera JL, Heyse JF. Testing the statistical certainty of a response to increasing doses of a drug. Biometrics 1985;41:295–301.
Author information
Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Vandenhende, F. Heart Rate-Specific Reference Ranges for QT-Interval in Beagle Dogs. Ther Innov Regul Sci 35, 1179–1188 (2001). https://doi.org/10.1177/009286150103500415
Published:
Issue Date:
Key Words
- QT interval
- QTc interval
- Heart rate
- Beagle dog
- Reference ranges