Heart Rate-Specific Reference Ranges for QT-Interval in Beagle Dogs

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. 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.

    CAS  Article  Google Scholar 

  2. 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.

    Google Scholar 

  3. 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.

    Google Scholar 

  4. 4.

    Funck-Brentano C, Jaillon P. Rate-corrected QT interval: techniques and limitations. Am J Cardiol 1993;72:17B–22B.

    CAS  Article  Google Scholar 

  5. 5.

    Bazett HC. An analysis of the time relationship of electrocardiograms. Heart 1920;7:353–380.

    Google Scholar 

  6. 6.

    Fridericia LS. Die systolendauer im elektrokardiogramm bei normalen menchen und bei herzkranken. Acta Med Scand 1920;53:469.

    Article  Google Scholar 

  7. 7.

    Mann WA, Kerns WD, Kinter LB. Normalization of Q. interval (QTc) in canine electrocardiography. Soc Toxicol Ann Mtg Proc 1994;14(1):376.

    Google Scholar 

  8. 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.

    Article  Google Scholar 

  9. 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.

    Article  Google Scholar 

  10. 10.

    Rutter C, Elashoff R. Analysis of longitudinal data: random coefficient regression modeling. Stat Med 1994;13:1211–1231.

    CAS  Article  Google Scholar 

  11. 11.

    Little R, Milliken G, Stroup W, Wolfinger, R. SAS System for Mixed Models. Cary, NC: SAS Institute Inc.; 1996:253–266.

    Google Scholar 

  12. 12.

    Royston P. Constructing time-specific reference ranges. Stat Med 1991;10:675–690.

    CAS  Article  Google Scholar 

  13. 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.

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Francois Vandenhende.

Rights and permissions

Reprints 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

Download citation

Key Words

  • QT interval
  • QTc interval
  • Heart rate
  • Beagle dog
  • Reference ranges