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

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus

Concentration time profiles of levofloxacin in plasma (a) and the change from pre‐dose QT interval corrected for heart rate by the Fridericia formula (ΔQTcF) over time (b) after dosing at six different clock times. Data are presented as mean ± 95% confidence intervals. Concentration time profiles were published previously.20 (c) The relationship between levofloxacin concentration and ΔQTcF after dosing at six different clock times, in which dots represent observed data points; lines and numbers show the estimated regression coefficients from a linear mixed effect model.
© Copyright Policy - creativeCommonsBy-nc
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5036421&req=5

psp412085-fig-0001: Concentration time profiles of levofloxacin in plasma (a) and the change from pre‐dose QT interval corrected for heart rate by the Fridericia formula (ΔQTcF) over time (b) after dosing at six different clock times. Data are presented as mean ± 95% confidence intervals. Concentration time profiles were published previously.20 (c) The relationship between levofloxacin concentration and ΔQTcF after dosing at six different clock times, in which dots represent observed data points; lines and numbers show the estimated regression coefficients from a linear mixed effect model.

Mentions: The concentration‐time profiles of levofloxacin in plasma and the change from pre‐dose QT interval ΔQTcF after administration of a 1,000 mg oral dose at six different time‐points are shown in Figure1a,b. There was a significant interaction between the effect of levofloxacin concentration and the effect of dosing time (P = 0.0319; linear mixed effects model), indicating that dosing time influences the relationship between levofloxacin concentration and ΔQTcF (Figure1c).


Levofloxacin ‐ Induced QTc Prolongation Depends on the Time of Drug Administration
Concentration time profiles of levofloxacin in plasma (a) and the change from pre‐dose QT interval corrected for heart rate by the Fridericia formula (ΔQTcF) over time (b) after dosing at six different clock times. Data are presented as mean ± 95% confidence intervals. Concentration time profiles were published previously.20 (c) The relationship between levofloxacin concentration and ΔQTcF after dosing at six different clock times, in which dots represent observed data points; lines and numbers show the estimated regression coefficients from a linear mixed effect model.
© Copyright Policy - creativeCommonsBy-nc
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5036421&req=5

psp412085-fig-0001: Concentration time profiles of levofloxacin in plasma (a) and the change from pre‐dose QT interval corrected for heart rate by the Fridericia formula (ΔQTcF) over time (b) after dosing at six different clock times. Data are presented as mean ± 95% confidence intervals. Concentration time profiles were published previously.20 (c) The relationship between levofloxacin concentration and ΔQTcF after dosing at six different clock times, in which dots represent observed data points; lines and numbers show the estimated regression coefficients from a linear mixed effect model.
Mentions: The concentration‐time profiles of levofloxacin in plasma and the change from pre‐dose QT interval ΔQTcF after administration of a 1,000 mg oral dose at six different time‐points are shown in Figure1a,b. There was a significant interaction between the effect of levofloxacin concentration and the effect of dosing time (P = 0.0319; linear mixed effects model), indicating that dosing time influences the relationship between levofloxacin concentration and ΔQTcF (Figure1c).

View Article: PubMed Central - PubMed

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.

No MeSH data available.


Related in: MedlinePlus