Contrasting Time- and Rate-Based Approaches for the Assessment of Drug-Induced QT Changes

¹ Cardiology Department, Lariboisière University Hospital
² AMPS LLC
³ Daiichi Sankyo Pharma Development

^* To whom correspondence should be addressed. E-mail: fabrice.extramiana{at}lrb.ap-hop-paris.fr.

	Abstract

The authors aim to highlight the pitfalls of different validated methods used for the assessment of drugs’ effect on QT duration. Digital 12-lead Holter electrocardiograms were recorded at baseline and after a single dose of sotalol in 39 healthy subjects (age = 27.4 ± 8.0 years). Using both time- and rate-based approaches, the authors obtained averaged QRS-T complexes every minute ("time bins") and at different RR intervals ("rate bins"). Time bins were corrected for heart rate using a subject-specific approach. The individual coefficients increased from placebo (0.309 ± 0.052) to sotalol (0.454 ± 0.136), P < .0001. When the placebo individual coefficients were applied to correct the QT interval on sotalol, the changes were > 5 ms smaller than those obtained using the ON drug coefficients. The "rate"-averaging process leads to a complete loss of the time course of drug effect. In conclusion, the individual correction formula calculated from the placebo condition cannot always be used for QT correction on the drug.
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