Highly automated QT measurement techniques in 7 thorough QT studies implemented under ICH E14 guidelines.
Thorough QT (TQT) studies are designed to evaluate potential effect of a novel drug on the ventricular repolarization process of the heart using QTc prolongation as a surrogate marker for torsades de pointes. The current process to measure the QT intervals from the thousands of electrocardiograms is lengthy and expensive. In this study, we propose a validation of a highly automatic-QT interval measurement (HA-QT) method. We applied a HA-QT method to the data from 7 TQT studies. We investigated both the placebo and baseline-adjusted QTc interval prolongation induced by moxifloxacin (positive control drug) at the time of expected peak concentration. The comparative analysis evaluated the time course of moxifloxacin-induced QTc prolongation in one study as well. The absolute HA-QT data were longer than the FDA-approved QTc data. This trend was not different between ECGs from the moxifloxacin and placebo arms: 9.6 ± 24 ms on drug and 9.8 ± 25 ms on placebo. The difference between methods vanished when comparing the placebo-baseline-adjusted QTc prolongation (1.4 ± 2.8 ms, P = 0.4). The differences in precision between the HA-QT and the FDA-approved measurements were not statistically different from zero: 0.1 ± 0.1 ms (P = 0.7). Also, the time course of the moxifloxacin-induced QTc prolongation adjusted for placebo was not statistically different between measurements methods.
Heart Research Follow-up Program, Cardiology Department, University of Rochester Medical Center, Rochester, NY 14642, USA. jean-philippe.couderc@heart.rochester.edu
Jean-Philippe
JP
Couderc
Christine
C
Garnett
Mike
M
Li
Robert
R
Handzel
Scott
S
McNitt
Xiajuan
X
Xia
Slava
S
Polonsky
Wojciech
W
Zareba
D000890:Anti-Infective Agents / Q000494:pharmacology; D001372:Aza Compounds / Q000494:pharmacology; D054715:Cardiotoxins; D004353:Drug Evaluation, Preclinical; D004562:Electrocardiography; D005260:Female; D024841:Fluoroquinolones; D017408:Guidelines as Topic; D006329:Heart Conduction System / Q000187:drug effects*; D006801:Humans; D008133:Long QT Syndrome / Q000139:chemically induced; D008297:Male; D008954:Models, Biological; D000077266:Moxifloxacin; D003473:Neuromuscular Nondepolarizing Agents / Q000008:administration & dosage; D011804:Quinolines / Q000494:pharmacology; D012737:Sex Factors
D000890:Anti-Infective Agents; D001372:Aza Compounds; D054715:Cardiotoxins; D024841:Fluoroquinolones; D003473:Neuromuscular Nondepolarizing Agents; D011804:Quinolines; D000077266:Moxifloxacin
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