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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.


Related in: MedlinePlus

Distribution of the conditional weighted residuals with interaction (CWRESI) and of interoccasional variability (IOV) on slope vs. time of day in a model in which the linear concentration‐effect relationship is constant over the 24 hours (a,b), includes 24 estimates of slope depending on the time of the electrocardiogram (ECG) recording (c,d), and is described by a cosine function with two harmonics with periods of 24 and 12 hours (e,f). Black lines in panels a, c, and e: nonparametric regression line (loess curve with span 0.6).
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psp412085-fig-0003: Distribution of the conditional weighted residuals with interaction (CWRESI) and of interoccasional variability (IOV) on slope vs. time of day in a model in which the linear concentration‐effect relationship is constant over the 24 hours (a,b), includes 24 estimates of slope depending on the time of the electrocardiogram (ECG) recording (c,d), and is described by a cosine function with two harmonics with periods of 24 and 12 hours (e,f). Black lines in panels a, c, and e: nonparametric regression line (loess curve with span 0.6).

Mentions: The development process of the drug‐effect model and corresponding changes in OFV are shown in Table1. A linear function best described the relationship between drug concentration and the QT interval, but a bias was observed in conditional weighted residuals vs. the time of day (Figure3a). Additionally, the distribution of the IOV on the concentration‐QT relationship depended on the time of drug administration (Figure3b). These biases could be corrected by estimating a separate value for the concentration‐QT relationship for each of the 24 hours (Figure3c,d). Alternatively, describing the concentration‐QT relationship by a cosine function with two harmonic terms with periods of 24 and 12 hours significantly improved the fit of the model and also corrected the bias in conditional weighted residuals over time of day and IOV (Figure3e,f). IOV was reduced to 0.3% and no longer affected the fit of the model.


Levofloxacin ‐ Induced QTc Prolongation Depends on the Time of Drug Administration
Distribution of the conditional weighted residuals with interaction (CWRESI) and of interoccasional variability (IOV) on slope vs. time of day in a model in which the linear concentration‐effect relationship is constant over the 24 hours (a,b), includes 24 estimates of slope depending on the time of the electrocardiogram (ECG) recording (c,d), and is described by a cosine function with two harmonics with periods of 24 and 12 hours (e,f). Black lines in panels a, c, and e: nonparametric regression line (loess curve with span 0.6).
© Copyright Policy - creativeCommonsBy-nc
Related In: Results  -  Collection

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

psp412085-fig-0003: Distribution of the conditional weighted residuals with interaction (CWRESI) and of interoccasional variability (IOV) on slope vs. time of day in a model in which the linear concentration‐effect relationship is constant over the 24 hours (a,b), includes 24 estimates of slope depending on the time of the electrocardiogram (ECG) recording (c,d), and is described by a cosine function with two harmonics with periods of 24 and 12 hours (e,f). Black lines in panels a, c, and e: nonparametric regression line (loess curve with span 0.6).
Mentions: The development process of the drug‐effect model and corresponding changes in OFV are shown in Table1. A linear function best described the relationship between drug concentration and the QT interval, but a bias was observed in conditional weighted residuals vs. the time of day (Figure3a). Additionally, the distribution of the IOV on the concentration‐QT relationship depended on the time of drug administration (Figure3b). These biases could be corrected by estimating a separate value for the concentration‐QT relationship for each of the 24 hours (Figure3c,d). Alternatively, describing the concentration‐QT relationship by a cosine function with two harmonic terms with periods of 24 and 12 hours significantly improved the fit of the model and also corrected the bias in conditional weighted residuals over time of day and IOV (Figure3e,f). IOV was reduced to 0.3% and no longer affected the fit of the 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.


Related in: MedlinePlus