Shortening of the QT Interval After Food Can Be Used to Demonstrate Assay Sensitivity in Thorough QT Studies

Abstract

The effect of food was investigated under conditions of a thorough QT (TQT) study and with confirmation of assay sensitivity by the use of a positive control (400 mg of moxifloxacin). Fifty-five healthy subjects were randomized to treatment and a sequence of fasted and fed baseline electrocardiography days. Subjects received standard breakfast 30 to 10 minutes prior to dosing. Measurement of QT interval was performed automatically with subsequent manual onscreen overreading using electronic calipers. A profound increase in heart rate of 9.4 bpm was observed in the fed condition compared with the fasted condition at 1.5 hours after dose with a corresponding shortening of QT (27 milliseconds); (baseline data). When corrected, QTcF interval was shortened significantly with the maximal effect observed at 2 hours after dose of 8.2 (95% confidence interval, 6-10) milliseconds. A concurrent shortening of the PR interval with a maximum value of 5.6 milliseconds was also observed. The findings of this study demonstrate that food alters the QT-RR relationship and shortens QTc and PR for at least 4 hours after a carbohydrate-rich meal. The findings are of regulatory interest as this study shows that normal physiological causes can shorten QTc significantly and that it could be used as a method to demonstrate assay sensitivity.