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 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.
Periclou
Antonia
A
Forest Research Institute, Harborside Financial Center, Plaza V, Jersey City, NJ 07311, USA. Antonia.Periclou@frx.com
Palmer
Robert H
RH
Zheng
Hongjie
H
Lindamood
Charles
C
D000293:Adolescent; D000328:Adult; D003521:Cyclopropanes / Q000494:pharmacology*; D004311:Double-Blind Method; D004562:Electrocardiography / Q000187:drug effects* / Q000379:methods; D005260:Female; D006329:Heart Conduction System / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D000078764:Milnacipran; D012189:Retrospective Studies; D013997:Time Factors; D055815:Young Adult
D003521:Cyclopropanes; D000078764:Milnacipran