A Thorough QT Study to Evaluate the Effects of a Supratherapeutic Dose of Sertraline on Cardiac Repolarization in Healthy Subjects

Abstract

The effect of steady‐state supratherapeutic sertraline (Zoloft) on QT interval was assessed in a single‐center, randomized, 3‐way crossover, double‐blind, placebo‐ and moxifloxacin‐controlled thorough QT study. Healthy adults received sertraline 400 mg/day, moxifloxacin 400 mg, and placebo, with a washout period (≥14 days) between treatments. A 12‐lead electrocardiogram was recorded in triplicate before dosing and at selected time points up to 72 hours after dosing. Analysis of covariance using a mixed‐effect model with sequence, period, treatment, time, and treatment‐by‐time interaction as fixed effects; subject within sequence as a random effect; and baseline QT corrected for heart rate using Fridericia formula (QTcF) as a covariate was conducted. A 90% confidence interval for the least squares (LS) mean difference in QTcF between active treatment and placebo was computed for each postdose time point. Exposure‐response was assessed using linear mixed‐effect modeling. Fifty‐four subjects were enrolled. Over 24 hours after dosing, the LS mean difference in QTcF for sertraline versus placebo ranged from 5.597 milliseconds to 9.651 milliseconds. The upper bound of the 90% confidence interval for the LS mean difference exceeded a predefined 10‐millisecond significance threshold at the 4‐hour postdose time point only (LS mean, 9.651 milliseconds [90% confidence interval, 7.635‐11.666]). In the exposure‐response analysis, QTcF values increased significantly with increasing sertraline concentration (slope = 0.036 milliseconds/ng/mL; P < .0001). Predicted change from baseline in QTcF at therapeutic maximum plasma sertraline concentration was 3.57 milliseconds. This thorough QTc study demonstrated a positive signal for QTc prolongation for sertraline at the steady‐state 400‐mg/day dose.

Role of Pharmacokinetics and Pharmacogenetics of Antidepressant-Induced Prolongation of the QT Interval and Torsade de Pointes in Patients with Mental Disorders

“…Most of the information analyzed in this review was obtained from retrospective studies [52, 70-72, 80, 126]. Prospective studies [74], especially consistent with level A evidence [102], have been sporadic. Studies rarely analyzed risk factors for QTc and TdP prolongation, such as age, gender, cardiovascular disease, and concomitant therapy.…”

“…In 4 of 9 studies, sertralineinduced prolongation of the QTc interval was not found [96][97][98]101]. However, 5 studies have demonstrated QTc prolongation from borderline values with therapeutic doses [44,78], which occur rarely [77], to a significant prolongation of the QTc interval with sertraline at toxic doses [102]. The latest study was conducted by the manufacturer and is grade A evidence [102].…”

“…However, 5 studies have demonstrated QTc prolongation from borderline values with therapeutic doses [44,78], which occur rarely [77], to a significant prolongation of the QTc interval with sertraline at toxic doses [102]. The latest study was conducted by the manufacturer and is grade A evidence [102]. At the same time, some authors did not find an increase in the risk of sertraline-induced SDS [78], other authors found rare cases of TdP [77] when taking sertraline.…”

Proteretic device: modelling and implementation in electronics and optical domain

“…across multiple domains, such as electrochemical domain for design of lithium ion batteries [4], in solar cells [5] and many other fields, proteresis too is a phenomenon observed in the magnetic topology of a dirac cone [6], the magnetic loop of a mixed spin Ising system [7] and in anti-ferromagnetic alloys [8,9]. It is also observed in nanoparticles like Cu 2 O/CuO and cobalt [10,11], polycrystalline-silicon thin-film transistors [12] and in different kinds of drugs used for pharmacokinetics and pharmacodynamics [13,14]. A reference model is studied for piezoelectric micro-positioning platform for high precision tracking and positioning applications [15].…”