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Effects of atomoxetine on the QT interval in healthy CYP2D6 poor metabolizers
Author(s) -
Loghin Corina,
Haber Harry,
Beasley Charles M.,
Kothare Prajakti A.,
Kauffman Lynnette,
April John,
Jin Ling,
Allen Albert J.,
Mitchell Malcolm I.
Publication year - 2013
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1111/j.1365-2125.2012.04382.x
Subject(s) - atomoxetine , moxifloxacin , placebo , confidence interval , qt interval , cyp2d6 , medicine , dosing , atomoxetine hydrochloride , anesthesia , attention deficit hyperactivity disorder , chemistry , methylphenidate , biochemistry , alternative medicine , pathology , cytochrome p450 , metabolism , psychiatry , antibiotics
Aim The effects of atomoxetine (20 and 60 mg twice daily), 400 mg moxifloxacin and placebo on QT c in 131 healthy CYP2D6 poor metabolizer males were compared. Methods Atomoxetine doses were selected to result in plasma concentrations that approximated expected plasma concentrations at both the maximum recommended dose and at a supratherapeutic dose in CYP2D6 extensive metabolizers. Ten second electrocardiograms were obtained for time‐matched baseline on days −2 and −1, three time points after dosing on day 1 for moxifloxacin and five time points on day 7 for atomoxetine and placebo. Maximum mean placebo‐subtracted change from baseline model‐corrected QT ( QT c M ) on day 7 was the primary endpoint. Results QT c M differences for atomoxetine 20 and 60 mg twice daily were 0.5 ms (upper bound of the one‐sided 95% confidence interval 2.2 ms) and 4.2 ms (upper bound of the one‐sided 95% confidence interval 6.0 ms), respectively. As plasma concentration of atomoxetine increased, a statistically significant increase in QT c was observed. The moxifloxacin difference from placebo met the a priori definition of non‐inferiority. Maximum mean placebo‐subtracted change from baseline QT c M for moxifloxacin was 4.8 ms and this difference was statistically significant. Moxifloxacin plasma concentrations were below the concentrations expected from the literature. However, the slope of the plasma concentration− QT c change observed was consistent with the literature. Conclusion Atomoxetine was not associated with a clinically significant change in QT c . However, a statistically significant increase in QT c was associated with increasing plasma concentrations.