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

Abstract

Viloxazine extended-release capsules (viloxazine ER; Qelbree) is a novel nonstimulant, recently approved by the US Food and Drug Administration for the treatment of ADHD in pediatrics. Here, we characterize the pharmacokinetics (PK) of viloxazine and its major metabolite, 5-HVLX-gluc, using a population PK model and evaluate the impact of 1-4 days of missed viloxazine ER doses on viloxazine PK. Data from 4 phase 3 trials in pediatric subjects treated with viloxazine ER were used to establish the PK model. Covariate analysis was conducted on the final base model. The impact of 1-4 days of missed doses on steady-state viloxazine PK was evaluated using Monte Carlo simulations. A 1-compartmental linear model with first-order absorption and elimination of the parent drug and first-order metabolite formation and elimination properly described the population PK of viloxazine and 5-HVLX-gluc. Body weight impacted the systemic exposure of viloxazine and 5-HVLX-gluc. Predicted PK parameters at steady state (mean ± standard deviation) in children receiving viloxazine ER were determined. C_max was 1.60 ± 0.70 μg/mL at 100 mg, 2.83 ± 1.31 μg/mL at 200 mg, and 5.61 ± 2.48 μg/mL at 400 mg. AUC_0-t was 19.29 ± 8.88 μg·h/mL at 100 mg, 34.72 ± 16.53 μg·h/mL at 200 mg, and 68.00 ± 28.51 μg·h/mL at 400 mg. PK parameters for adolescents receiving viloxazine ER were also determined. C_max was 2.06 ± 0.90 μg/mL at 200 mg, 4.08 ± 1.67 μg/mL at 400 mg, and 6.49 ± 2.87 μg/mL at 600 mg. AUC_0-t was 25.78 ± 11.55 μg·h/mL at 200 mg, 50.80 ± 19.76 μg·h/mL at 400 mg, and 79.97 ± 36.91 μg·h/mL at 600 mg. Simulations revealed that, regardless of the duration of the dosing interruption, viloxazine concentration returned to steady-state levels after approximately 2 days of once-daily dosing of viloxazine ER.

Keywords: ADHD; SPN-812; drug holiday; pharmacokinetics; population PK; viloxazine.

Figure 1

Schematic representation of the PK model for viloxazine and 5‐HVLX‐gluc. Viloxazine was well represented by a 1‐compartment model with first‐order absorption and elimination of the parent drug and first‐order metabolite formation and elimination. CLL, viloxazine clearance; CLV, viloxazine metabolic clearance; CLM, 5‐HVLX‐gluc clearance; k_a, viloxazine absorption rate constant.

Figure 2

Visual predictive checks. Observed and predicted viloxazine concentrations in children from study P303 (A) and adolescents from study P304 (B) administered viloxazine extended‐release at 200 and 400 mg/day, respectively. Individual observed values are represented by red‐filled circles, the median predicted values are represented by black diamonds and connected by the black lines, and the shaded light‐gray area represents the 90% prediction interval. Visual predictive checks for all studies and doses in children and adolescents are shown in Figures S2 and S3, respectively, in the supplemental materials.

Figure 3

Correlation of body weight with PK parameters. Correlation of body weight (in kilograms) with predicted volume of distribution (A), viloxazine clearance (B), viloxazine metabolic clearance (C), and 5‐HVLX‐gluc clearance (D).

Figure 4

Dose linearity of viloxazine PK parameters. Linear regression of viloxazine ER dose with viloxazine area under the curve (A), maximal concentration (B), and clearance (C). Blue‐shaded area represents the 95% confidence interval of the estimated regression line, and the dashed lines delimit the 95% prediction interval.

Figure 5

Predicted impact of drug holidays on viloxazine concentrations. Simulated viloxazine concentrations in children treated with 400 mg/day viloxazine extended release after 1, 2, 3, or 4 missed doses (A‐D, respectively). The median predicted values are represented by black diamonds and connected by the black lines, and the shaded light‐gray area represents the 90% prediction interval. The yellow‐shaded area within the dotted vertical lines represents the days of drug holiday.