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

Abstract

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.

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

“…The model used in the population PK analysis was a 1‐compartment model with first‐order absorption and elimination of the parent drug and first‐order metabolite formation and elimination, as shown in Figure 1. For full concentration‐over‐time plots over 72 hours, see recently reported studies in healthy adults 11,15,16 …”

“…A total of 495 subjects randomized to viloxazine ER treatment had sufficient PK samples to be included in the population PK analysis dataset: 86 subjects treated at the 100 mg dose level, 197 subjects treated at the 200 mg dose level, 164 subjects treated at the 400 mg dose level, and 48 subjects treated at the 600 mg dose level. Plasma concentrations of viloxazine and 5-HVLX-gluc were determined using validated liquid chromatography with tandem mass spectrometry (LC-MS/MS) (methods described in detail elsewhere 15,16 ). The lower limit of quantification was 0.01 µg/mL for viloxazine and 0.005 µg/mL for 5-HVLX-gluc.…”

“…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).…”

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

“…Exclusion criteria have been described in detail elsewhere. 24,25 To assess CYP2D6 metabolizer status, an oral buccal swab was used to collect DNA to be later extracted…”

“…Sample collection procedures have been previously described. 25 Briefly, blood samples for viloxazine PK were collected in period 1 (days 1-4) and period 3 (days 14-17) and were collected relative to SPN-812 administration at predose (baseline, time 0) and 0.5, 1, 2, 3, 4, 5,6,8,10,12,16,20,24,30,36,48,60, and 72 hours postdose. The actual time and date of each blood sample collection was recorded.…”