Levofloxacin‐Induced QTc Prolongation Depends on the Time of Drug Administration

Abstract

Understanding the factors influencing a drug's potential to prolong the QTc interval on an electrocardiogram is essential for the correct evaluation of its safety profile. To explore the effect of dosing time on drug‐induced QTc prolongation, a randomized, crossover, clinical trial was conducted in which 12 healthy male subjects received levofloxacin at 02:00, 06:00, 10:00, 14:00, 18:00, and 22:00. Using a pharmacokinetic‐pharmacodynamic (PK‐PD) modeling approach to account for variations in PKs, heart rate, and daily variation in baseline QT, we find that the concentration‐QT relationship shows a 24‐hour sinusoidal rhythm. Simulations show that the extent of levofloxacin‐induced QT prolongation depends on dosing time, with the largest effect at 14:00 (1.73 (95% prediction interval: 1.56–1.90) ms per mg/L) and the smallest effect at 06:00 (−0.04 (−0.19 to 0.12) ms per mg/L). These results suggest that a 24‐hour variation in the concentration‐QT relationship could be a potentially confounding factor in the assessment of drug‐induced QTc prolongation.