QT Effects of Duloxetine at Supratherapeutic Doses: A Placebo and Positive Controlled Study
| Autor: | Philip T Leese, Mary Pat Knadler, Jennie Lin Francis, David Hoelscher, Lu Zhang, J. T. Callaghan, Larry Ereshefsky, David S. Small, Durisala Desaiah, Celedon Gonzales, Jill Chappell, M. Derby, Mark Leibowitz |
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| Rok vydání: | 2007 |
| Předmět: |
Adult
Adolescent Moxifloxacin Thiophenes Duloxetine Hydrochloride Placebo QT interval law.invention Electrocardiography chemistry.chemical_compound Anti-Infective Agents Double-Blind Method Randomized controlled trial law medicine Humans Duloxetine Aged Pharmacology Aza Compounds Cross-Over Studies Dose-Response Relationship Drug Guideline adherence business.industry Age Factors Middle Aged Crossover study Antidepressive Agents chemistry Anesthesia Practice Guidelines as Topic Quinolines Female Guideline Adherence Cardiology and Cardiovascular Medicine business Fluoroquinolones medicine.drug |
| Zdroj: | Journal of Cardiovascular Pharmacology. 49:146-153 |
| ISSN: | 0160-2446 |
| DOI: | 10.1097/fjc.0b013e318030aff7 |
| Popis: | The electrophysiological effects of duloxetine at supratherapeutic exposures were evaluated to ensure compliance with regulatory criteria and to assess the QT prolongation potential.Electrocardiograms were collected in a multicenter, double-blind, randomized, placebo-controlled, crossover study that enrolled 117 healthy female subjects aged 19 to 74 years. Duloxetine dosages escalated from 60 mg twice daily to 200 mg twice daily; a single moxifloxacin 400 mg dose was used as a positive control. Data were analyzed using 3 QT interval correction methods: mixed-effect analysis of covariance model with RR interval change from baseline as the covariate, the QT Fridericia's correction method, and the individual QT correction method. Concentrations of duloxetine and its 2 major metabolites were measured.Compared with placebo, the mean change from baseline in QTc decreased with duloxetine 200 mg twice daily. The upper limits of the 2-sided 90% confidence intervals for duloxetine vs. placebo were0 msec at each time point by any correction method. No subject had absolute QT Fridericia's correction values445 msec with duloxetine, and the change in QT Fridericia's correction from baseline with duloxetine did not exceed 36 msec. No relationship was detected between QTc change and plasma concentrations of duloxetine or its metabolites even though average duloxetine concentrations ranged to more than 5 times those achieved at therapeutic doses. Moxifloxacin significantly prolonged QTc at all time points, regardless of correction method.Duloxetine does not affect ventricular repolarization as assessed by both mean changes and outliers in QT corrected by any method. |
| Databáze: | OpenAIRE |
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