Comparison of different QT correction methods for nonclinical safety assessment in ketamine-anesthetized Indian rhesus monkeys (Macaca mulatta)

Abstract

Rhesus monkeys are a non-rodent species employed in the preclinical safety evaluation of pharmaceuticals and biologics. These nonhuman primate species have been increasingly used in biomedical research because of the similarity in their ionic mechanisms of repolarization with humans. Heart rate and QT interval are two primary endpoints in determining the pro-arrhythmic risk of drugs. As heart rate and QT interval have an inverse relationship, any change in heart rate causes a subsequent change in QT interval. This warrants for calculation of a corrected QT interval. This study aimed to identify an appropriate formula that best corrected QT for change in heart rate. We employed seven formulas based on source-species type, clinical relevance, and requirements of various international regulatory guidelines. Data showed that corrected QT interval values varied drastically for different correction formulas. Equations were compared on their slope values based on QTc versus RR plots. The rank order of the slope for different formulas was (closest to farthest from zero) QTcNAK, QTcHAS, QTcBZT, QTcFRD, QTcVDW, QTcHDG, and QTcFRM. QTcNAK emerged to be the best correcting formula in this study. It showed the least correlation with the RR interval (r = −0.01) and displayed no significant difference amongst the sexes. As there is no universally recognized formula for preclinical use, the authors recommend developing a best-case scenario model for specific study designs and individual organizations. The data from this research will be helpful in deciding an appropriate QT correction formula for the safety assessment of new pharmaceuticals and biologics.

Keywords:

• Cardiovascular safety
• electrocardiography
• nonclinical
• QT correction method
• QT prolongation

Acknowledgements

The authors are grateful to the management and scientific team at Zydus Research Centre, Ahmedabad.

Ethical approval

All experimental procedures involving rhesus monkeys were approved by the Institutional Animal Ethics Committee and CCSEA (Committee for Control and Supervision of Experiments on Animals, Facility Registration Number: 77/PO/RcBi/SL/99/CPCSEA). CCSEA is a statutory committee under the Ministry of Fisheries, Animal Husbandry and Dairying, Government of India.

Author contributions

Laxit K. Bhatt: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Data Curation, Writing – Original Draft. Chitrang R. Shah: Methodology, Validation, Data Curation, Writing – Original Draft. Rajesh J. Patel: Investigation, Data Curation, Writing – Original Draft. Shital D. Patel: Methodology, Validation, Writing – Review and Editing. Sudhir R. Patel: Methodology, Data Curation, Writing – Review and Editing. Vipul A. Patel: Investigation, Validation, Writing – Original Draft. Jitendra H. Patel: Validation, Resources, Writing – Review and Editing, Supervision. Pankaj Dwivedi: Conceptualization, Validation, Investigation, Resources, Writing – Review and Editing, Project administration. Niraj A. Shah: Resources, Project administration. Rajesh S. Sundar: Writing – Review and Editing, Supervision. Mukul R. Jain: Writing – Review and Editing, Supervision.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.