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Br J Clin Pharmacol. 2014 Mar;77(3):522-31. doi: 10.1111/bcp.12201.

Are women more susceptible than men to drug-induced QT prolongation? Concentration-QTc modelling in a phase 1 study with oral rac-sotalol.

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1
Karolinska Institute, Department of Clinical Sciences, Danderyd's Hospital, Division of Cardiovascular Medicine, Stockholm, Sweden.

Abstract

AIM:

To study the differences in QTc interval on ECG in response to a single oral dose of rac-sotalol in men and women.

METHODS:

Continuous 12-lead ECGs were recorded in 28 men and 11 women on a separate baseline day and following a single oral dose of 160 mg rac-sotalol on the following day. ECGs were extracted at prespecified time points and upsampled to 1000 Hz and analyzed manually in a central ECG laboratory on the superimposed median beat. Concentration-QTc analyses were performed using a linear mixed effects model.

RESULTS:

Rac-sotalol produced a significant reduction in heart rate in men and in women. An individual correction method (QTc I) most effectively removed the heart rate dependency of the QTc interval. Mean QTc I was 10 to 15 ms longer in women at all time points on the baseline day. Rac-sotalol significantly prolonged QTc I in both genders. The largest mean change in QTc I (ΔQTc I) was greater in females (68 ms (95% confidence interval (CI) 59, 76 ms) vs. 27 ms (95% CI 22, 32 ms) in males). Peak rac-sotalol plasma concentration was higher in women than in men (mean Cmax 1.8 μg ml(-1) (range 1.1-2.8) vs. 1.4 μg ml(-1) (range 0.9-1.9), P = 0.0009). The slope of the concentration-ΔQTc I relationship was steeper in women (30 ms per μg ml(-1) vs. 23 ms per μg ml(-1) in men; P = 0.0135).

CONCLUSIONS:

The study provides evidence for a greater intrinsic sensitivity to rac-sotalol in women than in men for drug-induced delay in cardiac repolarization.

KEYWORDS:

PK/PD; QT prolongation; QT/QTc; gender; gender difference; rac-sotalol

PMID:
23819796
PMCID:
PMC4371537
DOI:
10.1111/bcp.12201
[Indexed for MEDLINE]
Free PMC Article
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