Impact of Paroxetine, a Strong CYP2D6 Inhibitor, on SPN‐812 (Viloxazine Extended‐Release) Pharmacokinetics in Healthy Adults

Abstract

SPN-812 (viloxazine extended-release) is a novel nonstimulant recently approved as a treatment for attentiondeficit/hyperactivity disorder in children and adolescents. Given that SPN-812 is metabolized by CYP2D6 and may be coadministered with CYP2D6 inhibitors, this trial investigated the pharmacokinetics and safety of SPN-812 coadministered with the potent CYP2D6 inhibitor paroxetine. In this single-sequence, 3-treatment period study in healthy volunteers, subjects received a single oral dose of 700 mg SPN-812 alone (period 1), 20 mg daily paroxetine (10 days, period 2), followed by concurrent administration of SPN-812 and paroxetine (period 3). Blood samples were collected for 72 hours post-SPN-812 dosing and analyzed for viloxazine and its primary metabolite, 5-HVLX-gluc. Twenty-two healthy adults were enrolled; all completed the trial. The potential for drug interaction between SPN-812 and paroxetine was assessed using analysis of variance on the log-transformed pharmacokinetic parameters C max , AUC 0-t , and AUC inf . The least-squares geometric mean ratios for viloxazine were (reported as the ratio of combination/SPN-812 alone) C max , 116.04%; 90%CI, 109.49%-122.99%; AUC 0-t , 134.65%; 90%CI, 127.65-142.03; and AUC inf , 134.80%; 90%CI, 127.94%-142.03%. CYP2D6 inhibition resulted in a modest change (<35%) on viloxazine AUCs with no change in C max . All adverse events were mild in severity.

Impact of a High-Fat Meal and Sprinkled Administration on the Bioavailability and Pharmacokinetics of Viloxazine Extended-Release Capsules (QelbreeTM) in Healthy Adult Subjects

“…Importantly, the dose used in the present study (200 mg) was lower than the higher 400–600 mg/day range used in adolescent and adult studies [ 25 – 27 ], and lower than the highest approved dose (400 mg/day) in pediatric patients [ 43 ]. Despite this, the T max reported here (5 h) is consistent with previous single-dose studies using viloxazine ER 700 mg in adults [ 30 , 33 , 34 ], and chronic once-daily doses of 100, 200, 400, and 600 mg in children and adolescents [ 44 ]. Because the pharmacokinetics of viloxazine appear to be linear across the therapeutic range (data on file), the pharmacokinetic effects demonstrated here are likely to be true at the higher end of the dosing range.…”

“…Based on the expected inter-and intrasubject variability of viloxazine, other similar studies [30][31][32], and FDA guidance [29], a sample size of 27 was deemed sufficient to assess the study endpoints.…”

Population Pharmacokinetics of Viloxazine Extended‐Release Capsules in Pediatric Subjects With Attention Deficit/Hyperactivity Disorder

“…For full concentration-over-time plots over 72 hours, see recently reported studies in healthy adults. 11,15,16 Bioavailability (F) was assumed to be equal to 1. The following parameters were used to jointly describe the viloxazine and 5-HVLX-gluc concentrations: the apparent volume of distribution of viloxazine (V2/F), the apparent volume of distribution of 5-HVLX-gluc (V3/F), the viloxazine absorption rate constant (k a ), the viloxazine clearance (CLL), the viloxazine metabolic clearance (CLV), and the 5-HVLX-gluc clearance (CLM).…”

“… 10 These in vitro data are consistent with a recent clinical drug interaction study in which CYP2D6 inhibition by paroxetine, a strong CYP2D6 inhibitor, resulted in a less than 35% increase in systemic viloxazine exposure, as measured by AUC. 11 Furthermore, another clinical study found only minimal impact of CYP2D6 genetic polymorphisms on systemic viloxazine exposure: C max increased only 20% and AUC 0‐24 increased 25% in poor CYP2D6 metabolizers, relative to extensive (normal) metabolizers. 12…”

“…13 Excess variability in drug exposure can result in significant changes to a drug's efficacy or safety profile, particularly in drugs with a narrow therapeutic index. Having been shown to be safe at high doses 4 , 5 , 11 , 14 , 15 , 16 and effective at improving ADHD symptoms and functional impairments even at lower doses, 2 , 3 , 17 viloxazine ER is thought to have a wide therapeutic window. However, even in drugs generally considered safe, drug exposure can be heavily influenced by missed or forgotten doses, body weight, body mass index (BMI), or factors altering hepatic metabolism.…”