Assessing Prolongation of the Corrected QT Interval with Bedaquiline and Delamanid Coadministration to Predict the Cardiac Safety of Simplified Dosing Regimens.

Delamanid and bedaquiline are two drugs approved to treat drug-resistant tuberculosis, and each have been associated with corrected QT interval (QTc) prolongation. We aimed to investigate the relationships between the drugs' plasma concentrations and the prolongation of observed QT interval corrected using Fridericia's formula (QTcF) and to evaluate their combined effects on QTcF, using a model-based population approach. Furthermore, we predicted the safety profiles of once daily regimens.

QT effects of bedaquiline, delamanid, or both in patients with rifampicin-resistant tuberculosis: a phase 2, open-label, randomised, controlled trial.

Background: Bedaquiline and delamanid are the first drugs of new classes registered for tuberculosis treatment in 40 years. Each can prolong the QTc interval, with maximum effects occurring weeks after drug initiation. The cardiac safety and microbiological activity of these drugs when co-administered are not well-established.

A Thorough QT/QTc Study With Laquinimod, a Novel Immunomodulator in Development for Multiple Sclerosis and Huntington Disease.

In this randomized double-blind study, 4 groups of healthy subjects (50 per arm) participated to evaluate the effect of laquinimod, an oral treatment in development for multiple sclerosis and Huntington disease, on the QTc interval. Subjects received a dose of either 0.6 or 1.

Effects of buprenorphine on QT intervals in healthy subjects: results of 2 randomized positive- and placebo-controlled trials.

Objectives: To study the effect of transdermal buprenorphine on QTc prolongation at dose levels of 10, 40, and 80 mcg/h, (BTDS 10, BTDS 40, BTDS 80).

Methods: Two randomized, placebo- and positive-controlled, parallel-group, dose-escalating clinical studies evaluated healthy adult subjects randomized to BTDS, placebo, or moxifloxacin in the first study; and to BTDS only, BTDS plus naltrexone, naltrexone alone at the same dose, placebo, or moxifloxacin in the second study. QT intervals were corrected for heart rate using data from each individual subject (QTcI).

Benefits of Centralized ECG Reading in Clinical Oncology Studies.

Background: Many clinical trials of investigational oncologic agents utilize electrocardiogram (ECG) machine measurements of QTc, for inclusion/exclusion and dosing decisions, though their reliability in this setting has not been established.

Methods: We compared the digital ECG machine QTc measurements with those obtained by a centralized ECG core lab on more than 270,000 consecutive ECGs collected from 299 clinical oncology trials.

Results: The mean difference between the ECG machine measurements and the central measured QTcF was 1.

Effect of single doses of IV palonosetron, up to 2.25 mg, on the QTc interval duration: a double-blind, randomized, parallel group study in healthy volunteers.

Purpose: The use of serotonin type 3 (5-HT3) receptor antagonists (RAs) in the prevention of nausea and vomiting caused by emetogenic chemotherapy is part of a comprehensive management strategy for patients undergoing chemotherapy. Electrocardiographic effects have been reported in patients after intravenous administration of 5-HT3 RAs. The present study investigated the electrocardiogram (ECG) profile of the 5-HT3 RA palonosetron following International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E14 Guidelines.

Moxifloxacin-induced QTc interval prolongations in healthy male Japanese and Caucasian volunteers: a direct comparison in a thorough QT study.

Aim: We investigated whether moxifloxacin-induced QTc prolongations in Japanese and Caucasian healthy male volunteers were significantly different.

Methods: A two period, randomized, crossover, ICH-E14-compliant thorough QT (TQT) study compared placebo-corrected changes in QTc interval from baseline (ΔΔQTc F) and concentration-effect relationships following administration of placebo and 400 mg moxifloxacin to 40 healthy male volunteers from each ethnic population. The point estimates of ΔΔQTc F for each population, and the difference between the two, were calculated at a geometric mean Cmax of moxifloxacin using a linear mixed effects model.

Update on Cardiovascular Safety of Tyrosine Kinase Inhibitors: With a Special Focus on QT Interval, Left Ventricular Dysfunction and Overall Risk/Benefit.

We previously reviewed the cardiovascular safety of 16 tyrosine kinase inhibitors (TKIs), approved for use in oncology as of 30 September 2012. Since then, the indications for some of them have been widened and an additional nine TKIs have also been approved as of 30 April 2015. Eight of these nine are indicated for use in oncology and one (nintedanib) for idiopathic pulmonary fibrosis.

Effect of bendamustine in combination with rituximab on QT interval duration in patients with advanced de novo indolent non-Hodgkin or mantle cell lymphoma.

Purpose: Bendamustine is used in chronic lymphocytic leukemia (first-line) and indolent B-cell non-Hodgkin lymphoma (NHL) that progressed during/within 6 months of treatment with rituximab or a rituximab-containing regimen. This study was a postapproval commitment to investigate bendamustine's effect on cardiac repolarization in treatment-naïve adults with advanced indolent NHL/mantle cell lymphoma (MCL).

Methods: In this multicenter, open-label, phase 3 study, patients received 6-8 28-day cycles of bendamustine (90 mg/m(2), days 1 and 2) and rituximab (375 mg/m(2), day 1).

Electrocardiographic response to intravenous and intraarterial injection of iosimenol (a new, iodinated, non-ionic, iso-osmolar contrast medium).

Serious arrhythmias, sometimes related to the injection of iodinated contrast media, are known complications of cardiac angiography. A new, iodine-based, non-ionic, iso-osmolar x-ray contrast media is in development for use in these procedures. This contrast medium, iosimenol, has a lower viscosity, higher electrolyte content, and higher iodine concentration than other available iso-osmolar contrast media.

Tyrosine kinase inhibitors: their on-target toxicities as potential indicators of efficacy.

Tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of certain forms of cancers, raising hopes for many patients with otherwise unresponsive tumours. While these agents are generally well tolerated, clinical experience with them has highlighted their unexpected association with serious toxic effects on various organs such as the heart, lungs, liver, kidneys, thyroid, skin, blood coagulation, gastrointestinal tract and nervous system. Many of these toxic effects result from downstream inhibition of vascular endothelial growth factor or epidermal growth factor signalling in cells of normal organs.

Hepatotoxicity of tyrosine kinase inhibitors: clinical and regulatory perspectives.

The introduction of small-molecule tyrosine kinase inhibitors (TKIs) in clinical oncology has transformed the treatment of certain forms of cancers. As of 31 March 2013, 18 such agents have been approved by the US Food and Drug Administration (FDA), 15 of these also by the European Medicines Agency (EMA), and a large number of others are in development or under regulatory review. Unexpectedly, however, their use has been found to be associated with serious toxic effects on a number of vital organs including the liver.

Cardiovascular safety of tyrosine kinase inhibitors: with a special focus on cardiac repolarisation (QT interval).

The development of tyrosine kinase inhibitors (TKI) represents a major milestone in oncology. However, their use has been found to be associated with serious toxicities that impinge on various vital organs including the heart. Sixteen TKIs have been approved for use in oncology as of 30 September 2012, and a large number of others are in development or under regulatory review.

Dealing with global safety issues : was the response to QT-liability of non-cardiac drugs well coordinated?

Drug-induced torsade de pointes (TdP) is a potentially fatal iatrogenic entity. Its reporting rate in association with non-cardiac drugs increased exponentially from the early 1990s and was associated with an increasing number of new non-cardiac drugs whose proarrhythmic liability was not appreciated pre-marketing. This epidemic provoked a comprehensive global response from drug regulators, drug developers and academia, which resulted in stabilization of the reporting rate of TdP.

Absence of QTc prolongation with betrixaban: a randomized, double-blind, placebo- and positive-controlled thorough ECG study.

Objective: To evaluate the effects of the anticoagulant betrixaban on individual heart rate-corrected QT (QTcI).

Research Design And Methods: Ninety-six healthy adults were randomly assigned to single-dose betrixaban 80 and 140 mg (therapeutic and supratherapeutic doses, respectively), placebo, and moxifloxacin 400 mg (positive control) in a four-period crossover study. Electrocardiograms were recorded at pre-dose and post-dose hours 1, 2, 3, 4, 5, 6, 8, 12, 16 and 24.

ICH E14 Q & A (R1) document: perspectives on the updated recommendations on thorough QT studies.

The International Conference on Harmonization (ICH) guidance ICH E14 provides recommendations, focusing on a clinical 'thorough QT/QTc (TQT) study', to evaluate the QT liability of a drug during its development. An Implementation Working Group (IWG) was also established to assist the sponsors with any uncertainties and clarify any ambiguities. In April 2012, the IWG updated its June 2008 version of the Questions and Answers document to address additional issues.

Early investigation of QTc liability: the role of multiple ascending dose (MAD) study.

The International Conference on Harmonization (ICH) guidance note E14 requires a thorough QT (TQT) study to characterize proactively the potential of a new drug to affect cardiac repolarization, as determined by prolongation of the corrected QT (QTc) interval. A typical TQT study is reviewed herein with a discussion on various practical issues concerning the use of a supratherapeutic dose, establishing assay sensitivity, the application of QT rate-correction methods, and restricting analyses of ECGs and plasma samples to key timepoints. We then discuss, and provide examples of, how multiple ascending dose (MAD) study protocols can be modified to integrate robust ECG monitoring and analyses to gather key information provided by a TQT study.

Midostaurin does not prolong cardiac repolarization defined in a thorough electrocardiogram trial in healthy volunteers.

Purpose: Midostaurin (PKC412) is a multitargeted tyrosine kinase inhibitor of FMS-like tyrosine kinase 3 receptor (FLT3), c-KIT, and other receptors. Midostaurin is active in patients with acute myeloid leukemia and systemic mastocytosis. Although no substantive risk for cardiac abnormalities has been observed with midostaurin in clinical studies thus far, some TKIs have been shown to affect cardiac repolarization.

Bupivacaine extended-release liposome injection exhibits a favorable cardiac safety profile.

Background And Objectives: Bupivacaine extended-release liposome injection is an investigational local analgesic intended for use in postsurgical pain management. In recognition of the incompletely characterized association of bupivacaine use and cardiac effects, this article reviews the cardiac safety profile of this novel formulation of bupivacaine.

Methods: Findings from paired electrocardiograms (ECGs), corresponding pharmacokinetic assessments, and cardiovascular adverse events (AEs) in a phase 2, randomized, double-blind, dose-ranging study of bupivacaine extended-release (150, 300, 450, or 600 mg) or bupivacaine HCl 150 mg with epinephrine administered intraoperatively via wound infiltration in patients undergoing total knee arthroplasty (n = 138), were assessed for potential causality.

No cardiac effects of therapeutic and supratherapeutic doses of rupatadine: results from a 'thorough QT/QTc study' performed according to ICH guidelines.

Aims: To evaluate the effects of therapeutic and supratherapeutic doses of rupatadine on cardiac repolarization in line with a 'thorough QT/QTc study' protocol performed according to International Conference on Harmonization guidelines.

Methods: This was a randomized (gender-balanced), parallel-group study involving 160 healthy volunteers. Rupatadine, 10 and 100 mg day(-1), and placebo were administered single-blind for 5 days, whilst moxifloxacin 400 mg day(-1) was given on days 1 and 5 in open-label fashion.

Arrhythmias in patients with chronic obstructive pulmonary disease (COPD): occurrence frequency and the effect of treatment with the inhaled long-acting beta2-agonists arformoterol and salmeterol.

Beta-adrenergic stimulation may increase heart rate and the potential for cardiac arrhythmias. The effect of inhaled long-acting beta2-agonists (LABAs) on these outcomes was evaluated in patients with chronic obstructive pulmonary disease (COPD) in 2 double-blind randomized clinical trials. The pretreatment arrhythmia occurrence frequency in these patients was also described.

Eletrocardiographic monitoring in COPD patients receiving tiotropium.

Tiotropium is a once-daily, inhaled anticholinergic for the treatment of chronic obstructive pulmonary disease that acts as a prolonged antagonist of the M3-receptor. To ascertain whether electrophysiologic effects can be detected following tiotropium treatment in patients with chronic obstructive pulmonary disease, serial electrocardiograms were incorporated into multiple placebo-controlled clinical trials including long-term (6 and 12-month) trials with tiotropium 18 mcg daily (n=2,128) and a 4-week dose-ranging study with tiotropium up to 36 mcg daily (n= 169). In addition, 24-hour electrocardiographic (Holter) monitoring was performed as part of a 6-week, placebo-controlled trial with tiotropium 18 mcg daily (n= 121).