Evaluation of the Effect of SPN-812 (Viloxazine Extended-Release) on QTc Interval in Healthy Adults

Nasser, Azmi; Faison, Shamia L.; Liranso, Tesfaye; Adewole, Toyin; Busse, Gregory D.; Fava, Maurizio; Kleiman, Robert B.; Schwabe, Stefan

doi:10.4088/jcp.20m13395

Cited by 16 publications

(14 citation statements)

References 20 publications

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“…There were no substantial differences between numbers of participants reporting AEs after treatment with viloxazine ER versus methylphenidate alone, nor when comparing viloxazine ER versus the combination. Although methylphenidate carries warnings of serious cardiovascular events [ 30 ], multiple clinical trials [ 25 – 29 ] and a recent study on cardiac repolarization [ 31 ] suggest viloxazine ER is not associated with increased cardiovascular risk, even at supratherapeutic doses. In the present study, the combination did not appear to increase these risks, as measured by blood pressure, pulse rate, or ECG parameters.…”

Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Coadministered Viloxazine Extended-Release (SPN-812) and Methylphenidate in Healthy Adults

et al. 2020

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Background and Objectives Viloxazine extended-release (viloxazine ER, SPN-812) is a novel non-stimulant with activity at serotonin receptors and the norepinephrine transporter, which is under investigation as a potential treatment for attention-deficit/hyperactivity disorder. Given the potential for viloxazine ER to be coadministered with other pharmacotherapies, this trial investigated the pharmacokinetics and safety of combination viloxazine ER + methylphenidate versus viloxazine ER or methylphenidate alone. Methods In this single-center, crossover, open-label trial, healthy adult participants received oral administration of 700 mg viloxazine ER alone, 36 mg methylphenidate alone, and combination viloxazine ER (700 mg) + methylphenidate (36 mg), with blood samples collected over 4 days post-administration. The active drug in viloxazine ER (viloxazine) and methylphenidate was measured using chromatographic tandem mass spectrometry. Safety assessments included adverse events (AEs), vital signs, echocardiograms, and clinical laboratory evaluations. Results Of 36 healthy adults who were enrolled, 34 completed the trial. The geometric least squares mean ratios are reported as [combination/single drug (90% confidence intervals)]. For viloxazine ER, maximum measured plasma concentration ( C max ) = 100.98% (96.21–105.99), area under the concentration–time curve from time zero to the last measurable time (AUC t ) = 98.62% (96.21–101.08), and area under the concentration–time curve from time zero to infinity (AUC ∞ ) = 98.96% (96.55–101.44). For methylphenidate, C max = 103.55% (97.42–110.07), AUC t = 106.67% (101.01–112.64), and AUC ∞ = 106.61% (100.99–112.54). All reported AEs were mild in severity. Conclusions Coadministration of viloxazine ER and methylphenidate did not impact the pharmacokinetics of viloxazine or methylphenidate relative to administration of either drug alone. The combination appeared to be safe and well tolerated.

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Section: Discussionmentioning

confidence: 99%

Pharmacokinetics of Coadministered Viloxazine Extended-Release (SPN-812) and Methylphenidate in Healthy Adults

et al. 2020

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“…dose of SPN-812 had no significant effect on cardiac repolarization or other ECG parameters, suggesting that it does not pose a risk of cardiac arrhythmias in healthy adults. 66 Cardiac AEs in SPN-812 Phase 3 study populations were infrequent, with only two incidences of tachycardia and one incidence of ECG T-wave inversion leading to discontinuation and considered related or possibly related to treatment across all four studies. [62][63][64][65] During intensive monitoring of suicidality, suicidal ideation and suicidal behavior were infrequent occurrences, with no incidence of suicidal ideation considered related to treatment and only one incidence of suicidal attempt in an SPN-812 treatment group considered possibly related to treatment.…”

Section: Viloxazinementioning

confidence: 95%

“…The study demonstrated that supratherapeutic (1800 mg q.d.) dose of SPN-812 had no significant effect on cardiac repolarization or other ECG parameters, suggesting that it does not pose a risk of cardiac arrhythmias in healthy adults 66 . Cardiac AEs in SPN-812 Phase 3 study populations were infrequent, with only two incidences of tachycardia and one incidence of ECG T-wave inversion leading to discontinuation and considered related or possibly related to treatment across all four studies 62-65 .…”

Section: Multimodal Agentsmentioning

confidence: 95%

Current and future nonstimulants in the treatment of pediatric ADHD: monoamine reuptake inhibitors, receptor modulators, and multimodal agents

et al. 2020

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Attention-deficit/hyperactivity disorder (ADHD), the single most common neuropsychiatric disorder with cognitive and behavioral manifestations, often starts in childhood and usually persists into adolescence and adulthood. Rarely seen alone, ADHD is most commonly complicated by other neuropsychiatric disorders that must be factored into any intervention plan to optimally address ADHD symptoms. With more than 30 classical Schedule II (CII) stimulant preparations available for ADHD treatment, only three nonstimulants (atomoxetine and extended-release formulations of clonidine and guanfacine) have been approved by the United States Food and Drug Administration (FDA), all of which focus on modulating the noradrenergic system. Given the heterogeneity and complex nature of ADHD in most patients, research efforts are identifying nonstimulants which modulate pathways beyond the noradrenergic system. New ADHD medications in clinical development include monoamine reuptake inhibitors, monoamine receptor modulators, and multimodal agents that combine receptor agonist/antagonist activity (receptor modulation) and monoamine transporter inhibition. Each of these “pipeline” ADHD medications has a unique chemical structure and differs in its pharmacologic profile in terms of molecular targets and mechanisms. The clinical role for each of these agents will need to be explored with regard to their potential to address the heterogeneity of individuals struggling with ADHD and ADHD-associated comorbidities. This review profiles alternatives to Schedule II (CII) stimulants that are in clinical stages of development (Phase 2 or 3). Particular attention is given to viloxazine extended-release, which has completed Phase 3 studies in children and adolescents with ADHD.

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“…In historic studies, viloxazine also did not increase the risk of adrenaline-induced cardiac arrhythmias [ 2 , 52 ]. In a contemporary study using supratherapeutic doses of viloxazine ER (1800 mg) in healthy adults, there was no effect on cardiac repolarization or other electrocardiogram parameters [ 54 ]. Minimal anticholinergic effects were found in human double-blind randomized studies of viloxazine 100 mg vs imipramine 50 mg [ 55 , 56 ], though both drugs induced transient tachycardia 4 h post-dose [ 55 ].…”

Section: Efficacy and Safety Of Viloxazine In Cns Conditions: Depression Anxiety Alcoholism And Epilepsymentioning

confidence: 99%

Viloxazine in the Management of CNS Disorders: A Historical Overview and Current Status

et al. 2021

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Viloxazine has a long history of clinical use in Europe as an antidepressant, and has recently been repurposed into an extended-release form for the treatment of attention-deficit/hyperactivity disorder in the USA. An immediate-release formulation was approved for the treatment of depression in the UK in 1974, and was subsequently marketed there and in several European countries for 30 years with no major safety concerns. In contrast to first-generation antidepressants (e.g., tricyclic antidepressants, monoamine oxidase inhibitors), viloxazine was associated with a relatively low risk for cardiotoxicity. Gastrointestinal symptoms were the most commonly reported side effects. The therapeutic effects of viloxazine are thought to be primarily the result of its action as a norepinephrine reuptake inhibitor, although in vitro and preclinical in vivo animal data suggest that viloxazine may also impact the serotoninergic system. This review summarizes the evolving knowledge of viloxazine based on information from previously published preclinical and clinical investigations, and acquired unpublished historical study reports from both open-label and blinded controlled clinical trials. We review the chemical properties, mechanism of action, safety, and tolerability across these studies, and discuss the contemporary rationale for the development of this agent as an extended-release oral formulation for the treatment of attention-deficit/hyperactivity disorder.

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Evaluation of the Effect of SPN-812 (Viloxazine Extended-Release) on QTc Interval in Healthy Adults

Cited by 16 publications

References 20 publications

Pharmacokinetics of Coadministered Viloxazine Extended-Release (SPN-812) and Methylphenidate in Healthy Adults

Pharmacokinetics of Coadministered Viloxazine Extended-Release (SPN-812) and Methylphenidate in Healthy Adults

Current and future nonstimulants in the treatment of pediatric ADHD: monoamine reuptake inhibitors, receptor modulators, and multimodal agents

Viloxazine in the Management of CNS Disorders: A Historical Overview and Current Status

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