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Methods Inf Med 2004; 43(05): 445-450
DOI: 10.1055/s-0038-1633895
Original Article
Schattauer GmbH

Correcting the QT Interval for Changes in HR in Pre-clinical Drug Development

M. Meyners
1   Department of Medical Data Services, Biostatistics Group, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
,
M. Markert
2   Department of Drug Discovery Support, General Pharmacology Group, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
05 February 2018 (online)

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Summary

Objectives: Estimation of possible cardiovascular side effects belongs to the safety assessment of every drug candidate. Drug-induced prolongation of the QT interval can result in life-threatening ventricular arrhythmia. In pre-clinical drug development, animal experiments are used to study this possible effect. Researchers have become aware that correction formulae derived for human beings are not applicable to animal experiments.

Methods: We investigated some of the proposed models by comparing the outcomes of the analyses on the same data. The data was derived from telemetry measurements on Labrador dogs. We propose the use of both the correlation with heart rate (or RR interval) and a measure of predictive performance. As a sufficiently large number of observations were available, the data was subdivided into a training and a test set. The training set serves to estimate the respective parameters while the test set is used to determine the performance of the model. Here, a kind of PRESS statistic was used. Next, the models were considered for treated animals, using the estimated parameters. Both positive and negative controls were used.

Conclusions: Most models under consideration performed quite well. These models eliminated the correlation for the most part and were reasonably predictive. Furthermore, they reliably differentiate between positive and negative controls. The next steps in identifying the best correction will be to consider additional compounds as well as other species to validate our current results.

Keywords

QT prolongation - correction formulae - comparison - prediction
 

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