Referenced in: none

Automatically associated channels: Kv11.1

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

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

Journal, date & volume: Int J Clin Pharmacol Ther, 2013 Dec , 51, 948-57

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/24120715

Abstract
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.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.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.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.