Key result
Atomoxetine 20 and 60 mg twice daily produced maximum mean placebo-subtracted QTc changes of 0.5 ms and 4.2 ms, respectively, which were not clinically significant.
Why the study?
Does atomoxetine increase the QT interval compared to placebo in healthy CYP2D6 poor metabolizer males?
RCT (n=131)
Does atomoxetine increase the QT interval compared to placebo in healthy CYP2D6 poor metabolizer males?
Atomoxetine at doses up to 60 mg twice daily does not cause clinically significant QT prolongation in healthy CYP2D6 poor metabolizers, though a concentration-dependent increase in QTc was observed.
Atomoxetine poses no clinically significant QT risk in CYP2D6 poor metabolizers; confirms cardiac safety in this high-exposure RCT population.
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.
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Loghin et al. (2012) conducted an RCT in Healthy CYP2D6 poor metabolizers (n=131). Atomoxetine vs. Placebo was evaluated on Maximum mean placebo-subtracted change from baseline model-corrected QT (QT(c)M) on day 7 (MD 4.2 ms, 95% CI upper bound 6.0). Atomoxetine 20 and 60 mg twice daily produced maximum mean placebo-subtracted QTc changes of 0.5 ms and 4.2 ms, respectively, which were not clinically significant.
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