Viloxazine extended-release for ADHD not linked to adverse cardiac outcomes
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Viloxazine extended-release did not appear associated with risk for cardiac arrhythmias or other electrocardiographic parameters, according to study results published in Journal of Clinical Psychiatry.
“[Viloxazine] is a multimodal serotonergic and noradrenergic modulating agent with demonstrated activity at serotonin receptors and the norepinephrine transporter,” Azmi Nasser, PhD, of Supernus Pharmaceuticals Inc. in Maryland, and colleagues wrote. “In vivo, viloxazine has been shown to increase serotonin (5-HT), norepinephrine and dopamine levels in the prefrontal cortex, a region strongly implicated in the ADHD pathophysiology. In vitro, viloxazine exhibits antagonistic activity at 5-HT2C receptors, although the downstream effects of this activity remain to be fully elucidated.”
Previous studies have shown links between effects on cardiac repolarization and psychotropic agent use. According to the investigators, evaluating potentially severe consequences of drug-induced effects on cardiac repolarization (QTc) is essential during clinical development of novel agents.
In the current double-blind, randomized, crossover design study, Nasser and colleagues sought to determine the QTc effects of a supratherapeutic dose of viloxazine extended-release among 24 healthy adults. Participants received a three-treatment sequence of placebo, 400 mg moxifloxacin and 1,800 mg viloxazine for 2 consecutive days, separated by a washout of 3 days. The correlation between change from baseline in individual heart rate corrected QT interval and viloxazine and 5-hydroxyviloxazine glucuronide (5-OH-VLX-gluc) plasma concentrations (Cps) served as the primary endpoint. The time point placebo-adjusted change from baseline in individual heart rate corrected QT interval served as the secondary endpoint. The investigators also analyzed and reported changes in electrocardiogram morphology, as well as other safety parameters.
Results showed a statistically significant negative slope (P = .0012) for the correlation between change from baseline in individual heart rate corrected QT interval and viloxazine Cp, as well for 5-OH-VLX-gluc and change from baseline in individual heart rate corrected QT interval (P = .0007). According to secondary time point analyses, viloxazine extended-release appeared to have no effect on individual heart rate corrected QT interval. Further, the researchers noted confirmation of assay sensitivity with moxifloxacin and acceptable safety parameters.
“The cardiovascular safety of [viloxazine extended-release] can be an important factor in the selection of treatment options for patients with ADHD,” Nasser and colleagues wrote. “The obvious limitation of this study is the 2-day dosing tested in healthy adult volunteers, and more ECGs need to be collected long-term in the targeted populations.”