How can we further improve individual QT correction methods: an application of Chronobiology
28 Feb 2012

Authors: Simon Authier (CiToxLAB North America), Abdel-Ilah El Amrani (CiToxLAB France) and Christina Skytte (CiToxLAB Denmark), Roy Forster (CiToxLAB France)

Quantification of QT has been a major safety consideration in the last decade in safety pharmacology.
As a surrogate for torsade de pointe, QT prolongation remains a central experimental endpoint during early or GLP investigations. Efforts to increase sensitivity for arrythmogenic potential detection range from study design to monitoring conditions and analysis methods.

Circadian rhythms are evidenced through various parameters monitored continuously by telemetry (e.g. cardiovascular, respiratory, EEG, sleep stages, body temperature, etc.). The diurnal QT-RR relationship is different from the nocturnal correlation of these two parameters.
Individual QT correction methods normally assume a stable relationship between QT and RR.

We evaluated the impact of separate diurnal and nocturnal individual corrections on corrected QT.

Material and Methods

Telemetry data from 8 male Beagle dogs monitored for at least 48 hours were used to calculate QTca based on the method described by Spence et al. for the entire monitoring period.

Telemetry data from 12 cynomolgus monkeys (10 males and 2 females) were subjected to the same analysis.
Calculations were then performed separately for each animal for diurnal and nocturnal periods. The results were also compared with standard correction formulas.

Results

The average slopes of linear regression for corrected QT in canines as a function of heart rate for standard correction formulas were 0.1560 ± 0.0637 msec/bpm for QTcF and 0.0469 ± 0.01914 msec/bpm for QTcV.
The average slope of linear regression for QTca as a function of heart rate in the same species was -0.0221 ± 0.0039 msec/bpm compared to -0.0098 ± 0.0024 when individual corrections were calculated separately for diurnal and nocturnal periods (p<0.05).

In cynomolgus monkeys, the individual QT correction based on separate diurnal and nocturnal correlations was superior to the individual QT correction based on the entire monitoring period for 73.1% of the data.

Discussion

Diurnal fluctuations in autonomic tone are recognized to correlate with changes in QT-RR relationship in telemetered animals (Soloviev et al., 2006).
Individual QT correction is recognized to provide superior results compared to standard correction formulas.

A number of drug candidates inducing QT alterations also present severe chronotropic effects.
Separate QT-RR calculations for diurnal and nocturnal periods may reduce heart rate induced changes in QTca by up to 1 msec in presence of chronotropic effects and help better quantify the risk associated with the test compound.

Conclusion

Calculation of individual QTc for diurnal and nocturnal periods may help refine quantification of repolarization changes in some cases such as when significant chronotropic effects are present.

References

- Spence S, Soper K, Hoe CM, Coleman J. The heart rate-corrected QT interval of conscious beagle dogs: a formula based on analysis of covariance. Toxicol Sci. 1998:247-58.
- Soloviev MV, Hamlin RL, Barrett RM, Chengelis CP, Schaefer GJ. Different species require different correction factors for the QT interval. Cardiovasc Toxicol. 2006:145-57.