Are women more susceptible than men to drug‐induced QT prolongation? Concentration–QTc modelling in a phase 1 study with oral rac‐sotalol. (March 2014)

• Record Type: Journal Article
• Authors: Darpo, Borje; Karnad, Dilip R.; Badilini, Fabio; Florian, Jeff; Garnett, Christine E; Kothari, Snehal; Panicker, Gopi Krishna; Sarapa, Nenad
• Is Part Of: British journal of clinical pharmacology. Volume 77:Number 3(2014:Mar.)
• Page Start: 522
• Page End: 531
• Publication Date: 2014-03
• Subjects: Pharmacology -- Periodicals; Drugs -- Periodicals; 615.1
• DOI: 10.1111/bcp.12201
• Languages: English
• ISSNs: 0306-5251

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <sec id="bcp12201-sec-0001" sec-type="section"> <title>Aim</title> <p>To study the differences in QT<sub>c</sub> interval on ECG in response to a single oral dose of rac‐sotalol in men and women.</p> </sec> <sec id="bcp12201-sec-0002" sec-type="section"> <title>Methods</title> <p>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.</p> </sec> <sec id="bcp12201-sec-0003" sec-type="section"> <title>Results</title> <p>Rac‐sotalol produced a significant reduction in heart rate in men and in women. An individual correction method (QT<sub>c</sub>I) most effectively removed the heart rate dependency of the QT<sub>c</sub> interval. Mean QT<sub>c</sub>I was 10 to 15 ms longer in women at all time points on the baseline day. Rac‐sotalol significantly prolonged QT<sub>c</sub>I in both genders. The largest mean change in QT<sub>c</sub>I (ΔQT<sub>c</sub>I) was greater in females (68 ms (95% confidence interval (CI) 59, 76 ms) <italic>vs</italic>. 27 ms (95% CI 22, 32 ms) in males). Peak rac‐sotalol plasma concentration was higher in women than in men (mean <italic>C</italic><sub>max</sub> 1.8 μg ml<sup>−1</sup> (range 1.1–2.8) <italic>vs</italic>. 1.4 μg ml<sup>−1</sup> (range 0.9–1.9), <italic>P</italic> = 0.0009). The slope of the concentration–ΔQT<sub>c</sub>I relationship was steeper in women (30 ms per μg ml<sup>−1</sup><italic>vs.</italic> 23 ms per μg ml<sup>−1</sup> in men; <italic>P</italic> = 0.0135).</p> </sec> <sec id="bcp12201-sec-0004" sec-type="section"> <title>Conclusions</title> <p>The study provides evidence for a greater intrinsic sensitivity to rac‐sotalol in women than in men for drug‐induced delay in cardiac repolarization.</p> </sec> </abstract>