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High-quality triplicate electrocardiogram monitoring in a first-in-man study: potential for early detection of drug-induced QT prolongation

Yan-Ling He, Yiming Zhang, Jing-He Yan, Wei Zhou, Steven Komjathy and Ann Taylor

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Volume 51 p. 948 - 957

Abstract

International Journal of Clinical Pharmacology and Therapeutics, Vol. 51 – No. 12/2013 (948-957)

High-quality triplicate electrocardiogram monitoring in a first-in-man study: potential for early detection of drug-induced QT prolongation

Yan-Ling He¹, Yiming Zhang², Jing-He Yan², Wei Zhou², Steven Komjathy³ and Ann Taylor¹

¹Novartis Institutes for BioMedical Research, Cambridge, MA, ²Novartis, East Hanover, NJ, and ³Charles River Clinical Services Northwest Inc., Tacoma, WA, USA
Background: QT interval prolongation is associated with an increased risk of potentially fatal ventricular tachycardias, including torsade de pointes. Regulatory guidance recommends the “thorough QT/QTc” (TQT) study as the gold standard for assessing the propensity of novel nonantiarrhythmic drugs to delay cardiac repolarization. An opportunity exists, however, to use high-quality electrocardiogram (ECG) data from first-in-man trials as an exploratory and complementary approach to gain early insight into potential risk of QT prolongation. Methods: We collected high-quality, triplicate, 12-lead ECG data during a first-in-man trial of a drug developed for the treatment of Type 2 diabetes that had shown in vitro hERG inhibition and potential to prolong QT intervals in an animal model. Results: QTc prolongation was observed at the highest dose, leading to a maximum QTcF prolongation > 19 ms at 6 hours after the 14th daily dose. QTcF increases from time-matched baseline relative to placebo were positively correlated with peak plasma concentrations. Conclusions: Clinically relevant QT interval prolongations can be detected during first-in-man studies using high-quality ECG monitoring. Such data may facilitate early decision making on whether to terminate the development of a compound and invest resources in more promising molecules; and it may enable more efficient TQT study design or preclude the need for future TQT studies.Correspondence to:
Yan-Ling He, PhD, DMSc
Translational Medicine
Novartis Institutes for BioMedical Research
220 Massachusetts Avenue, Building 605
Cambridge, MA, 02139-3584, USA
Email: [email protected]

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