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Evaluation of the Effect of 5 QT‐Positive Drugs on the JTpeak Interval — An Analysis of ECGs From the IQ‐CSRC Study
Author(s) -
Darpo Borje,
Benson Charles,
Brown Randy,
Dota Corina,
Ferber Georg,
Ferry Jim,
Jarugula Venkat,
Keirns James,
OrtemannRe Catherine,
Pham Thuan,
Riley Steve,
Sarapa Nenad,
Ticktin Mark,
Zareba Wojciech,
Couderc JeanPhilippe
Publication year - 2020
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1002/jcph.1502
Subject(s) - dofetilide , ondansetron , medicine , qt interval , herg , moxifloxacin , cardiology , anesthesia , proarrhythmia , bradycardia , heart rate , nausea , blood pressure , potassium channel , microbiology and biotechnology , biology , antibiotics
The JTpeak interval has been proposed as a new biomarker to demonstrate mixed ion channel effects, potentially leading to reduced late‐stage electrocardiogram (ECG) monitoring for mildly QT‐prolonging drugs. ECG waveforms from the IQ‐CSRC study were used. Twenty healthy subjects were enrolled with 6 subjects on placebo and 9 subjects on each of 5 mildly QT‐prolonging drugs — moxifloxacin, dofetilide, ondansetron, dolasetron, and quinine — and 1 negative drug, levocetirizine. A vector magnitude lead was derived from 12‐lead ECGs, and measurements were made on a median beat from three 10‐second replicates. Data were analyzed using a linear concentration‐response model with QTcF and heart rate corrected JTpeak (JTpeak_c) as dependent variables. For moxifloxacin, dofetilide, and ondansetron, all pure hERG blockers, slopes of the concentration (C)‐QTcF and C‐JTpeak_c relationships were positive and statistically significant. With the prespecified linear model, the predicted effects on ΔΔQTcF and ΔΔJTpeak_c were 11.4 and 9.4 milliseconds for moxifloxacin at the geometric mean C max on day 1, 9.0 and 11.7 milliseconds for dofetilide and 11.5, and 7.9 milliseconds for ondansetron, respectively. In contrast, dolasetron and quinine, both with additional ion channel effects, prolonged QTcF with a positive C‐ΔQTcF slope and predicted ΔΔQTcF effect on day 1 of 6.2 and 11.4 milliseconds, whereas the C‐ΔJTpeak_c slope and the predicted ΔΔJTpeak on day 1 were negative (−0.3 and −7.5 milliseconds per ng/mL). Pure hERG‐blocking drugs prolonged both the QTc and the JTpeak_c intervals, whereas drugs with mixed ion channel effects, including peak sodium inhibition, prolonged QTcF but not the JTpeak_c interval.