QT Effects of Duloxetine at Supratherapeutic Doses: A Placebo and Positive Controlled Study

Zhang, Lu; Chappell, Jill; Gonzales, Celedon; Small, David S.; Knadler, Mary Pat; Callaghan, John T.; Francis, Jennie; Desaiah, Durisala; Leibowitz, Mark; Ereshefsky, Larry; Hoelscher, David; Leese, Philip T.; Derby, Michael A.

doi:10.1097/fjc.0b013e318030aff7

Cited by 55 publications

(38 citation statements)

References 38 publications

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“…7 Published literature on TQT studies tend to use both therapeutic and supratherapeutic doses in the characterization of cardiac repolarization effects. [10][11][12][13][14][15][16] Recently, Iwamoto et al 10 sufficient in the data analysis. 10 In addition, in cases where there appears to be an effect of a drug on QT interval, considerable added value can be gained by characterizing the concentration-QT relationships in a quantitative fashion to provide interpretations whether the observed effects are clinically meaningful.…”

Section: Discussionmentioning

confidence: 98%

A Thorough QTc Study to Assess the Effect of Sitagliptin, a DPP4 Inhibitor, on Ventricular Repolarization in Healthy Subjects

Bloomfield

Krishna

Hreniuk

et al. 2009

The Journal of Clinical Pharma

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A randomized, double-blind, placebo-controlled, 4-period crossover study was performed with a single oral dose of sitagliptin (100 mg, 800 mg), moxifloxacin (400 mg), and placebo in order to provide a rigorous assessment of the effect of sitagliptin on ventricular repolarization based on the ICH E14 guidance. The clinical dose of sitagliptin 100 mg was not associated with an increase in QTc interval, corrected using the Fridericia correction (QTcf), at any time point. The supratherapeutic 800-mg dose of sitagliptin was generally well tolerated and was associated with minimal, clinically insignificant prolongation of the QTcf interval at concentrations approximately 11-fold higher than maximal concentrations following the 100-mg clinical dose. The PK/QTc model demonstrated a shallow relationship between the plasma concentration of sitagliptin and the placebo-subtracted QTcf change from baseline, with a 0.59-millisecond increase in QTc for every 1000-nM increment in sitagliptin plasma concentration. The sensitivity of the assay to detect modest increases in QTc interval was established with the active control moxifloxacin. In conclusion, at clinically relevant concentrations, sitagliptin is not associated with clinically meaningful QTcf prolongation.

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Section: Discussionmentioning

confidence: 98%

A Thorough QTc Study to Assess the Effect of Sitagliptin, a DPP4 Inhibitor, on Ventricular Repolarization in Healthy Subjects

Bloomfield

Krishna

Hreniuk

et al. 2009

The Journal of Clinical Pharma

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“…There are, however, a few studies in which only a supratherapeutic dose of the NCE was included (Iwamoto et al 2008;Krishnaswami et al 2011;Vourvahis et al 2012;Zhang et al 2007). This approach is obviously sufficient if results are clearly negative.…”

Section: Study Populationmentioning

confidence: 97%

Clinical ECG Assessment

Darpö

2015

Principles of Safety Pharmacology

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With the adoption of the ICH E14 guidance, the thorough QT/QTc (TQT) study has become the focus of clinical assessment of an NCE's effects on ECG parameters. The TQT study is used as a guide to the liability of a drug to cause proarrhythmias on the basis of delayed cardiac repolarization. Around 300 TQT studies have been performed since 2005 and through interactions between sponsors and regulators, especially FDA's Interdisciplinary Review Team (IRT) for QT studies. These studies can today be performed more effectively and with great confidence in the generated data. This chapter will discuss technical features and the design and analysis of TQT studies, how assay sensitivity is demonstrated, and examples from recently conducted studies. ECG assessment for drugs that cannot be safely given to healthy volunteers is also addressed, and examples from studies in cancer patients and in healthy volunteers with tyrosine kinase inhibitors are discussed. The TQT study is resource intensive and designed to solely evaluate whether an NCE prolongs the QTc interval. If data with similar confidence can be generated from other studies that are routinely performed as part of the clinical development, this would represent a more optimal use of human resources. Methods and approaches to increase the confidence in ECG data derived from "early QT assessment" in single-ascending/multiple-ascending dose studies are therefore discussed, and a path toward replacing the TQT study using these approaches will be outlined.

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“…The issue of prolongation of the corrected QT interval of the electrocardiogram (QTc) was addressed in a study in healthy female volunteers [88] in which supratherapeutic exposures to duloxetine (initially 120 mg, which was stepped up to 240 mg then to 320 mg and finally 400 mg) were compared with 400 mg moxifloxacin (a drug known to prolong QTc interval). Overall, the mean QTc …”

Section: Vital Signs and Cardiovascular Effectsmentioning

confidence: 99%

Duloxetine in the acute and continuation treatment of major depressive disorder

Bochsler

Olver

Norman

2011

Expert Review of Neurotherapeutics

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Duloxetine is a serotonin-noradrenaline reuptake inhibitor with indications for use in the short term, continuation and maintenance treatment of major depression. Although clinicians currently have access to a range of medications for the treatment of depression, a significant number of patients fail to respond or remit from their illness despite adequate trials of treatment with multiple agents. A developing concept is that antidepressant strategies that combine multiple mechanisms of action may have advantages over agents with single mechanisms (i.e., selective serotonin reuptake inhibitors). As a dual-acting agent, duloxetine offers the promise of advantages in terms of efficacy over selective serotonin reuptake inhibitors while retaining a favorable safety and tolerability profile in comparison to older agents. Likewise, duloxetine is of interest in the treatment of certain conditions commonly seen in conjunction with major depression, particularly anxiety and pain, both of which may respond more favorably to agents that act on both serotonin and noradrenaline neurotransmitter systems.

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QT Effects of Duloxetine at Supratherapeutic Doses: A Placebo and Positive Controlled Study

Abstract: Duloxetine does not affect ventricular repolarization as assessed by both mean changes and outliers in QT corrected by any method.

Cited by 55 publications

References 38 publications

A Thorough QTc Study to Assess the Effect of Sitagliptin, a DPP4 Inhibitor, on Ventricular Repolarization in Healthy Subjects

A Thorough QTc Study to Assess the Effect of Sitagliptin, a DPP4 Inhibitor, on Ventricular Repolarization in Healthy Subjects

Clinical ECG Assessment

Duloxetine in the acute and continuation treatment of major depressive disorder

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