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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.


Twenty‐four‐hour variation in slope. Dots: median ± 95 prediction intervals derived from 500 bootstrap runs of the model in which a separate value for slope was estimated for each of the 24 hours. Solid black line: estimated cosine function from the model with fixed baseline parameters, with the light gray area representing the 95% prediction interval derived from 500 bootstrap runs.
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psp412085-fig-0004: Twenty‐four‐hour variation in slope. Dots: median ± 95 prediction intervals derived from 500 bootstrap runs of the model in which a separate value for slope was estimated for each of the 24 hours. Solid black line: estimated cosine function from the model with fixed baseline parameters, with the light gray area representing the 95% prediction interval derived from 500 bootstrap runs.

Mentions: The values of the concentration‐QT relationship from the model in which this relationship was estimated independently for each of the 24 hours had a low level of precision, but followed a sinusoidal‐like pattern over time, with higher values in the afternoon and lower values in the early morning (Figure4, dots). This pattern was closely matched by the model in which the concentration‐QT relationship was described by a two harmonic cosine function (Figure4, line). The cosine model was selected over the model with 24 separate estimates because of a lower Akaike information criterion (Δ Akaike information criterion = −6), indicating a better trade‐off between model complexity (number of model parameters) and fit of the data. Additionally, providing a continuous description of the variation in the concentration‐QT relationship over the 24‐hour period, the cosine model has more predictive value than the other model.


Levofloxacin ‐ Induced QTc Prolongation Depends on the Time of Drug Administration
Twenty‐four‐hour variation in slope. Dots: median ± 95 prediction intervals derived from 500 bootstrap runs of the model in which a separate value for slope was estimated for each of the 24 hours. Solid black line: estimated cosine function from the model with fixed baseline parameters, with the light gray area representing the 95% prediction interval derived from 500 bootstrap runs.
© Copyright Policy - creativeCommonsBy-nc
Related In: Results  -  Collection

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

psp412085-fig-0004: Twenty‐four‐hour variation in slope. Dots: median ± 95 prediction intervals derived from 500 bootstrap runs of the model in which a separate value for slope was estimated for each of the 24 hours. Solid black line: estimated cosine function from the model with fixed baseline parameters, with the light gray area representing the 95% prediction interval derived from 500 bootstrap runs.
Mentions: The values of the concentration‐QT relationship from the model in which this relationship was estimated independently for each of the 24 hours had a low level of precision, but followed a sinusoidal‐like pattern over time, with higher values in the afternoon and lower values in the early morning (Figure4, dots). This pattern was closely matched by the model in which the concentration‐QT relationship was described by a two harmonic cosine function (Figure4, line). The cosine model was selected over the model with 24 separate estimates because of a lower Akaike information criterion (Δ Akaike information criterion = −6), indicating a better trade‐off between model complexity (number of model parameters) and fit of the data. Additionally, providing a continuous description of the variation in the concentration‐QT relationship over the 24‐hour period, the cosine model has more predictive value than the other model.

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.