Abstract

Understanding the physiological fluctuations in the corrected QT (QTc) interval is important to accurately interpret the variations in drug-induced prolongation. The present study aimed to define the time course of the effect of moxifloxacin on the QT interval to understand the duration of the responses to moxifloxacin. This retrospective analysis was performed on data taken from a thorough QT 4-way crossover study with 40 subjects. Each period consisted of a baseline electrocardiogram (ECG) day (day -1) and a treatment day (day 1). On both days, ECGs were recorded simultaneously using 2 different systems operating in parallel: a bedside ECG and a continuous Holter recording. The subjects were randomized to 1 of 4 treatments: 5 mg and 40 mg of intravenous amisulpride, a single oral dose of moxifloxacin (400 mg), or placebo. Standardized meals, identical in all 4 periods, with similar nutritional value were served. Bedside ECG results confirmed that the moxifloxacin peak effect was delayed in the fed state and showed that the Fridericia corrected QT prolongation induced by moxifloxacin persisted until the end of the 24-hour measurement period. The use of continuous Holter monitoring provided further insight, as it revealed that the moxifloxacin effect on QTc was influenced by diurnal and nocturnal environmental factors, and hysteresis effects were noticeable. The findings suggested that moxifloxacin prolongs QTc beyond its elimination from the blood circulation. This is of relevance to current concentration-effect modeling approaches, which presume the absence of hysteresis effects.