QT effects of duloxetine at supratherapeutic doses: a placebo and positive controlled study.
BACKGROUND
The electrophysiological effects of duloxetine at supratherapeutic exposures were evaluated to ensure compliance with regulatory criteria and to assess the QT prolongation potential.


METHODS
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.


RESULTS
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 were <0 msec at each time point by any correction method. No subject had absolute QT Fridericia's correction values >445 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.


CONCLUSIONS
Duloxetine does not affect ventricular repolarization as assessed by both mean changes and outliers in QT corrected by any method.
Zhang
Lu
L
Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. lu.zhang@lilly.com
Chappell
Jill
J
Gonzales
Celedon R
CR
Small
David
D
Knadler
Mary P
MP
Callaghan
J T
JT
Francis
Jennie L
JL
Desaiah
Durisala
D
Leibowitz
Mark
M
Ereshefsky
Larry
L
Hoelscher
David
D
Leese
Philip T
PT
Derby
Michael
M
D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000890:Anti-Infective Agents / Q000494:pharmacology; D000928:Antidepressive Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D000068736:Duloxetine Hydrochloride; D004562:Electrocardiography / Q000187:drug effects*; D005260:Female; D024841:Fluoroquinolones; D019983:Guideline Adherence; D006801:Humans; D008875:Middle Aged; D000077266:Moxifloxacin; D017410:Practice Guidelines as Topic; D011804:Quinolines / Q000494:pharmacology; D013876:Thiophenes / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
D000890:Anti-Infective Agents; D000928:Antidepressive Agents; D001372:Aza Compounds; D024841:Fluoroquinolones; D011804:Quinolines; D013876:Thiophenes; D000068736:Duloxetine Hydrochloride; D000077266:Moxifloxacin