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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

(a) The relationship between the RR interval and the QTc interval in pre‐dose electrocardiogram (ECG) recordings after correction for heart rate with the coefficient estimated by the baseline model (α = 0.216). The line shows the regression coefficient estimated by a linear mixed effect model. (b) Variation in pre‐dose QTc interval over the time of day. The line shows the shape of the cosine function estimated by the baseline model. (a and b) The dots show observed data.
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psp412085-fig-0002: (a) The relationship between the RR interval and the QTc interval in pre‐dose electrocardiogram (ECG) recordings after correction for heart rate with the coefficient estimated by the baseline model (α = 0.216). The line shows the regression coefficient estimated by a linear mixed effect model. (b) Variation in pre‐dose QTc interval over the time of day. The line shows the shape of the cosine function estimated by the baseline model. (a and b) The dots show observed data.

Mentions: To correct for potential 24‐hour variation in the baseline QT interval and for study‐specific dependency of the QT interval on heart rate, a baseline model was developed. The parameter estimates of this model are shown in Supplementary Table S1. A proportional error structure was used to describe the residual error. IIV and IOV were included on the intercept of the QT‐RR relationship (QT0). A one harmonic cosine function with a period of 24 hours best described the variation in the baseline QT interval over the course of the day (ΔOFV −15; P < 0.01; 2 df). Inclusion of an additional harmonic with a period of 12 hours did not further improve the fit of the model (ΔOFV −3.1; P > 0.05; 2 df vs. model with 24‐hour cosine). Accounting for this 24‐hour variation in the baseline QT interval decreased the IOV on QT0 from 3% to 2.3% and removed a bias observed in the conditional weighted residuals over time of day (Supplementary Figure S1). Estimation of a separate value of α during sleep did not significantly improve the fit of the model (ΔOFV −6.2; P > 0.01; 1 df). This baseline model adequately removed the dependency of the QTc interval on the RR, as evidenced by the nonsignificant effect of RR on QTc (P = 0.49; linear mixed effects model), and described the 24‐hour variation in the QTc intervals of the baseline data (Figure2).There was no indication that the relationship between the QT and RR interval depends on the time of day (Supplementary Figure S2).


Levofloxacin ‐ Induced QTc Prolongation Depends on the Time of Drug Administration
(a) The relationship between the RR interval and the QTc interval in pre‐dose electrocardiogram (ECG) recordings after correction for heart rate with the coefficient estimated by the baseline model (α = 0.216). The line shows the regression coefficient estimated by a linear mixed effect model. (b) Variation in pre‐dose QTc interval over the time of day. The line shows the shape of the cosine function estimated by the baseline model. (a and b) The dots show observed data.
© Copyright Policy - creativeCommonsBy-nc
Related In: Results  -  Collection

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

psp412085-fig-0002: (a) The relationship between the RR interval and the QTc interval in pre‐dose electrocardiogram (ECG) recordings after correction for heart rate with the coefficient estimated by the baseline model (α = 0.216). The line shows the regression coefficient estimated by a linear mixed effect model. (b) Variation in pre‐dose QTc interval over the time of day. The line shows the shape of the cosine function estimated by the baseline model. (a and b) The dots show observed data.
Mentions: To correct for potential 24‐hour variation in the baseline QT interval and for study‐specific dependency of the QT interval on heart rate, a baseline model was developed. The parameter estimates of this model are shown in Supplementary Table S1. A proportional error structure was used to describe the residual error. IIV and IOV were included on the intercept of the QT‐RR relationship (QT0). A one harmonic cosine function with a period of 24 hours best described the variation in the baseline QT interval over the course of the day (ΔOFV −15; P < 0.01; 2 df). Inclusion of an additional harmonic with a period of 12 hours did not further improve the fit of the model (ΔOFV −3.1; P > 0.05; 2 df vs. model with 24‐hour cosine). Accounting for this 24‐hour variation in the baseline QT interval decreased the IOV on QT0 from 3% to 2.3% and removed a bias observed in the conditional weighted residuals over time of day (Supplementary Figure S1). Estimation of a separate value of α during sleep did not significantly improve the fit of the model (ΔOFV −6.2; P > 0.01; 1 df). This baseline model adequately removed the dependency of the QTc interval on the RR, as evidenced by the nonsignificant effect of RR on QTc (P = 0.49; linear mixed effects model), and described the 24‐hour variation in the QTc intervals of the baseline data (Figure2).There was no indication that the relationship between the QT and RR interval depends on the time of day (Supplementary Figure S2).

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&#8208;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&#8208;pharmacodynamic (PK&#8208;PD) modeling approach to account for variations in PKs, heart rate, and daily variation in baseline QT, we find that the concentration&#8208;QT relationship shows a 24&#8208;hour sinusoidal rhythm. Simulations show that the extent of levofloxacin&#8208;induced QT prolongation depends on dosing time, with the largest effect at 14:00 (1.73 (95% prediction interval: 1.56&ndash;1.90) ms per mg/L) and the smallest effect at 06:00 (&minus;0.04 (&minus;0.19 to 0.12) ms per mg/L). These results suggest that a 24&#8208;hour variation in the concentration&#8208;QT relationship could be a potentially confounding factor in the assessment of drug&#8208;induced QTc prolongation.

No MeSH data available.


Related in: MedlinePlus