Dr Kothare's work on this manuscript was performed while employed by Eli Lilly and Company; her present employer is Merck & Co., Inc.
Effects of atomoxetine on the QT interval in healthy CYP2D6 poor metabolizers
Article first published online: 10 JAN 2013
© 2012 Eli Lilly and Company. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society
British Journal of Clinical Pharmacology
Volume 75, Issue 2, pages 549–564, February 2013
How to Cite
Loghin, C., Haber, H., Beasley, C. M., Kothare, P. A., Kauffman, L., April, J., Jin, L., Allen, A. J. and Mitchell, M. I. (2013), Effects of atomoxetine on the QT interval in healthy CYP2D6 poor metabolizers. British Journal of Clinical Pharmacology, 75: 549–564. doi: 10.1111/j.1365-2125.2012.04382.x
- Issue published online: 10 JAN 2013
- Article first published online: 10 JAN 2013
- Accepted manuscript online: 16 JUL 2012 09:39AM EST
- Manuscript Accepted: 1 JUL 2012
- Manuscript Received: 7 FEB 2012
- Eli Lilly and Company (Indianapolis, IN, USA)
- ICH E14;
- thorough QT
The effects of atomoxetine (20 and 60 mg twice daily), 400 mg moxifloxacin and placebo on QTc in 131 healthy CYP2D6 poor metabolizer males were compared.
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 (QTcM) on day 7 was the primary endpoint.
QTcM 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 QTc was observed. The moxifloxacin difference from placebo met the a priori definition of non-inferiority. Maximum mean placebo-subtracted change from baseline QTcM 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−QTc change observed was consistent with the literature.
Atomoxetine was not associated with a clinically significant change in QTc. However, a statistically significant increase in QTc was associated with increasing plasma concentrations.