Effects of Milnacipran on Cardiac Repolarization in Healthy Participants

Milnacipran is approved for management of fibromyalgia in the United States. In this double‐blind, placebo‐ and active drug‐controlled study (N = 100), effects of supratherapeutic doses of milnacipran on cardiac repolarization were evaluated in healthy volunteers. The primary outcome was the largest...

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Bibliographic Details
Published in:Journal of clinical pharmacology 2010-04, Vol.50 (4), p.422-433
Main Authors: Periclou, Antonia, Palmer, Robert H., Zheng, Hongjie, Lindamood III, Charles
Format: Article
Language:English
Subjects:
Adolescent
Adult
cardiac repolarization
Cardiology
Confidence intervals
Cyclopropanes - pharmacology
Double-Blind Method
Electrocardiography
Electrocardiography - drug effects
Electrocardiography - methods
Female
fibromyalgia
Heart Conduction System - drug effects
Heart Conduction System - physiology
Heart rate
Heart Rate - drug effects
Heart Rate - physiology
Humans
Male
Middle Aged
milnacipran
QTc interval
Retrospective Studies
Time Factors
Young Adult
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Summary:Milnacipran is approved for management of fibromyalgia in the United States. In this double‐blind, placebo‐ and active drug‐controlled study (N = 100), effects of supratherapeutic doses of milnacipran on cardiac repolarization were evaluated in healthy volunteers. The primary outcome was the largest mean difference between milnacipran and placebo in time‐matched baseline‐adjusted QT interval corrected for heart rate using an individual correction formula (QTcNi). In addition, data were analyzed using the Fridericia formula (QTcF) and a post hoc piecewise QTcNi analysis based on a dichotomous cut of RR interval data at 800 ms. Moxifloxacin (400 mg single dose) was used to establish assay sensitivity. Using the QTcNi method, the largest difference in baseline‐adjusted QTcNi between milnacipran 300 mg bid and placebo was −4.7 ms (90% confidence interval [CI]: −9.4 to −0.1), indicating no QT prolongation. Analysis using the Fridericia formula (QTcF) showed a maximum adjusted mean change of +7.7 ms, but QTcF versus RR interval plots indicated overcorrection with this method. The piecewise QTcNi correction method demonstrated a more accurate correction for drug‐induced heart rate increase; mean baseline‐adjusted between‐group difference was +0.9 ms (90% CI: −6.6 to 8.3). The results suggest that milnacipran would not significantly affect cardiac repolarization at clinically relevant therapeutic and supratherapeutic concentrations.
ISSN:0091-2700
1552-4604
DOI:10.1177/0091270009346059