What Is Already Known About This Subject: Some non-anti-arrhythmic drugs delay cardiac repolarization, which can be measured as an increase in the QT interval. Delays in cardiac repolarization create an electrophysiological environment that favours the development of cardiac arrhythmias, which may lead to torsade de pointes, which can be fatal. As part of the clinical development of eltrombopag, a thorough QT(c) study was conducted to evaluate the effects of eltrombopag on cardiac repolarization at both therapeutic and supratherapeutic doses and to characterize the relationship between plasma eltrombopag concentrations and change in QT(c).

What This Study Adds: This study found no clinically significant QT prolongation for eltrombopag when administered as 50 mg or 150 mg every day for 5 days. There were no safety or tolerability signals of clinical concern. A small incidence of ventricular premature beats was observed, but this was consistent with previously reported incidences in healthy volunteers without apparent heart disease.

Aim: To evaluate the effect of eltrombopag on cardiac repolarization and to characterize the relationship between plasma eltrombopag concentrations and change in QT(c).

Methods: This was a double-blind, placebo- and active-controlled, randomized, balanced four-period, crossover study in healthy men and women. Subjects were randomized to receive eltrombopag 50 mg and 150 mg, moxifloxacin 400 mg (positive control) and placebo in one of four sequences.

Results: Eighty-seven subjects entered the study and 48 completed. There was no prolongation of QT(c) (Fridericia) following eltrombopag treatment, as the upper limit of the 90% confidence interval (CI) for the time-matched change from baseline in QT(c)F between drug and placebo (ddQT(c)F) did not exceed 10 ms for eltrombopag at either dose. Maximum observed mean treatment difference was 2.29 ms (90% CI 0.34, 4.24) for eltrombopag 150 mg at 1 h post-dose and 11.64 ms (90% CI 9.64, 13.64) for moxifloxacin 400 mg at 4 h. Eltrombopag C(max) and AUC(0,24 h) increased in a dose proportional manner between 50 mg and 150 mg after 5 days' dosing. Proportions of subjects with adverse events were similar across treatments (52-66% of subjects). Most withdrawals (26/39 subjects) were due to elevated platelets. Three subjects were withdrawn for ventricular premature beats (one following each active treatment) reported as related to the study drug.

Conclusions: No clinically significant QT(c) prolongation was observed for eltrombopag at therapeutic and supratherapeutic doses.

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2909804PMC
http://dx.doi.org/10.1111/j.1365-2125.2010.03646.xDOI Listing

Publication Analysis

Top Keywords

cardiac repolarization
20
eltrombopag
13
qtc study
8
study healthy
8
eltrombopag cardiac
8
therapeutic supratherapeutic
8
supratherapeutic doses
8
characterize relationship
8
relationship plasma
8
plasma eltrombopag
8

Similar Publications

Aims: Decrease in repolarizing K+ currents, particularly the fast component of transient outward K+ current (Ito,f), prolongs action potential duration (APD) and predisposes the heart to ventricular arrhythmia during cardiac hypertrophy. Histone deacetylases (HDACs) have been suggested to participate in the development of cardiac hypertrophy, and class I HDAC inhibition has been found to attenuate pathological remodeling. This study investigated the potential therapeutic effects of HDAC2 on ventricular arrhythmia in pressure overload-induced cardiac hypertrophy.

View Article and Find Full Text PDF

This is a case of a young, 20-year-old, male Navy recruit who was admitted to our healthcare facility with intermittent atypical chest pain and limiting exertional symptoms and was diagnosed with myocardial bridging (MB) as the most likely etiology of his chest after the complete cardiac workup, leading to his career limitations due to potential risks. Our patient presented with atypical chest pain and limiting exertional symptoms. Chest pain was non-radiating.

View Article and Find Full Text PDF

This analysis assessed the relationship between the plasma concentrations of loperamide and its N-desmethyl loperamide meta- bolite (M1) and the potential QT interval prolongation at therapeutic and supratherapeutic doses. The exposure-response analysis was performed using the data from healthy adults participating in a randomized, double-blind, single-dose, four-way (placebo; loperamide 8 mg [therapeutic]; loperamide 48 mg [supratherapeutic]; moxifloxacin 400 mg [positive control]) crossover study. The electrocardiographic measurements extracted from 12-lead digital Holter recordings were time-matched to pharmacokinetic sampling of loperamide/M1.

View Article and Find Full Text PDF

The impact of Celiac Disease (CD) is not only limited to the intestinal system, but extraintestinal manifestations may also be seen. In this context, cardiac manifestations have recently been the focus of attention. This study aimed to evaluate myocardial repolarization properties in CD patients by assessing the frontal QRS-T Angle (fQRS-T) on electrocardiography (ECG).

View Article and Find Full Text PDF

A randomized, partially blinded, placebo-controlled, crossover study in 48 healthy adults assessed the effect of momelotinib on the heart rate-corrected QT interval (QTc) using the Fridericia formula (QTcF). QTc was evaluated for momelotinib 200 mg (therapeutic dose), momelotinib 800 mg (supratherapeutic dose), moxifloxacin 400 mg (positive control), and placebo. Pharmacokinetic profiles of momelotinib and its active metabolite M21 were evaluated.

View Article and Find Full Text PDF

Want AI Summaries of new PubMed Abstracts delivered to your In-box?

Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!