Evaluation of the Effect of 5 QT-Positive Drugs on the JTpeak Interval - An Analysis of ECGs From the IQ-CSRC Study.

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 Cmax 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.

Improving the precision of QT measurements.

BACKGROUND: Accurate and precise QT interval measurement is very important for both regulatory and drug developmental decision making. These measurements are often made using a manual or semi-automated technique, and the associated variability necessitates sample sizes of around 50 to 70 subjects in thorough QT/QTc studies. The purpose of this study was to compare the reproducibility and precision of a semi-automated (SA) method and a high-precision (HPQT) technique for ECG extraction and QT interval measurement on two thorough QT/QTc (TQT) studies conducted in compliance with ICH E14. METHODS: Data from 35 healthy subjects from two different crossover TQT studies on treatment with placebo and moxifloxacin was analyzed. Both methods examined the RR and QT intervals measured in lead II or the lead with the highest quality T-wave on a single beat basis using the QT algorithm included in the COMPAS software package. ECGs were measured at a protocol-specific timepoint. RESULTS: The effect of moxifloxacin on the QTc interval was highly reproducible in the two studies, and assay sensitivity was met with both methods. Pairwise comparison of QTcF values between methods demonstrated high agreement with no bias, small mean differences (below 1.5 ms) and narrow limits of agreement. HPQT improved the precision of the QTc measurement by 31% in Study I (standard deviation of DQTcF: SA 8.9 ms; HPQT 6.3 ms) and by 15% in Study II (SD: SA 9.7 ms; HPQT 8.3 ms). CONCLUSIONS: The HPQT QT measurement technique detected the effect induced by moxifloxacin with the same accuracy as SA techniques, and with clearly improved precision. More precise QTc measurement has important implications in terms of lowering the likelihood of false positive results and/or reducing the sample size in TQT studies, as well as improving the utility of QT assessment in early clinical development.