Characterization of the Human QT Interval: Novel Distribution‐Based Assessment of the Repolarization Effects of Moxifloxacin

Abstract

The authors have previously demonstrated rate-independent QT variability in the dog and cynomolgus monkey, where the QT associated with any RR was a normally distributed value that was accurately evaluated as the distribution mean. The present study investigated the rate-independent characteristics of the human QT. Digital electrocardiographs (1000 Hz) were collected for 24 hours in 51 patients (thorough QT study) and analyzed by computer. Distribution-based analysis was applied to the placebo and moxifloxacin (400 mg) arms to characterize the nature of the QT interval and to assess the efficacy of distribution-based analysis for QTc determination. Novel statistics using continuous means and bootstrapped 95% confidence intervals were developed to facilitate QT analysis. Machine-read QT values were compared with core laboratory semiautomated values for verification. RR intervals demonstrated repetitive protocol-dependent variations (50-250 milliseconds); QT intervals were normally distributed, spanning 60 to 100 milliseconds for each RR interval. Distribution-based analysis detected a moxifloxacin response identical to semiautomated analysis, but with reduced variability and improved statistical power, where n = 12 satisfied the ICH E14 criteria for a positive control. Distribution-based analysis has the potential to provide a universal method for clinical QT heart rate correction, enabling accurate detection of QT changes when limited numbers of volunteers are exposed to drug.

Diurnal Profile of the QTc Interval Following Moxifloxacin Administration

“…The mean QTcF values derived at equivalent time points did not differ systematically from the bedside ECG results. The peak effect of moxifloxacin exposure is seen after a delay of 4 hours after dosing with a point estimate (90%CI) of 11.6 milliseconds (9.4, 13.8 milliseconds), which is due to the moxifloxacin dose being administered after breakfast, leading to a delay in absorption and additionally to a direct reduction of the moxifloxacin PK and QTc effect …”

“…Of note was the observed QTc prolongation at the 12‐ and 24‐hour time points. Even though this is a common observation, it is rarely discussed in the literature.…”

“…32 Of note was the observed QTc prolongation at the 12-and 24-hour time points. Even though this is a common observation, 33,34 it is rarely discussed in the literature. In the present report, we used continuous analysis based on Holter recordings to investigate a potential relationship between diurnal variations in QTc interval and the magnitude of the effect of moxifloxacin.…”

“…In the same study by Bloomfield et al, the QTc interval remained elevated above the predose baseline value for up to 48 hours after the dose, with values above the 10‐millisecond threshold at 18 hours. Holzgrefe et al highlighted the need to further express the data as the time‐matched change from placebo (double delta) to clearly ascertain the treatment effect and showed a similar raised QT interval up to 24 hours following treatment with moxifloxacin, despite the excellent correlation between the QTc double delta and moxifloxacin plasma levels (r 2 = 0.83).…”

Telemetric assessment of social and single housing: Evaluation of electrocardiographic intervals in jacketed cynomolgus monkeys

“…ECG waveforms were processed through ECGPRO (DSI, St Paul, MN) post acquisition analysis software to remove signal noise and filtered to remove non-physiologic values. Individual animal QT rate corrections (QTca) were determined during the jacket acclimation period for each group to ascertain each animal's unique QT/RR relationship (Holzgrefe et al, 2012). Such individual rate corrections were applied to all data from all caging types to correct for QT variations associated with heart rate.…”