Premium
QT interval analyses from a placebo and positive controlled study evaluating the electrophysiological effects of duloxetine at supratherapeutic doses
Author(s) -
Zhang L.,
Derby M.,
Gonzales C.,
Chappell J.,
Lucas R.,
Small D.,
Knadler M. P.,
Callaghan J. T.
Publication year - 2005
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1016/j.clpt.2004.11.048
Subject(s) - duloxetine , moxifloxacin , qt interval , placebo , medicine , duloxetine hydrochloride , confidence interval , anesthesia , crossover study , cardiology , alternative medicine , pathology , microbiology and biotechnology , biology , antibiotics
Background/Aims The electrophysiological effects of duloxetine at supratherapeutic exposures were evaluated to ensure compliance with regulatory criteria and to definitively establish the absence of QT/QTc prolongation. Methods ECGs were collected in a multicenter, double blind, randomized, placebo‐controlled, crossover study which enrolled 117 healthy female subjects aged 19–74 years. Duloxetine dosages escalated from 60 mg BID to 200 mg BID; moxifloxacin 400 mg was a positive control. The primary analysis was of QTcF (Fridericia's correction) based on a mixed‐effect ANOVA model evaluated at the 200‐mg BID level. Secondary analyses included a mixed‐effect ANCOVA model with RR change from baseline as the covariate and an individual QT correction approach. Results Compared with placebo, the mean change from baseline in QTc decreased with duloxetine 200 mg BID. The upper limits of the 2‐sided 90% confidence intervals for duloxetine vs placebo were <0 msec at each time point by any correction method. Absolute QTcF values and the change in QTcF from baseline with duloxetine did not exceed 445 msec and 36 msec, respectively. No relationship was detected between QTc change and plasma concentrations of duloxetine or its metabolites. Moxifloxacin significantly prolonged QTc at all time points, regardless of correction method. Conclusions Duloxetine does not adversely affect ventricular repolarization as assessed by both mean changes and outliers in QT corrected by any correction method. Clinical Pharmacology & Therapeutics (2005) 77 , P12–P12; doi: 10.1016/j.clpt.2004.11.048