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

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 mu g/mL at 100 mg, 2.83 +/- 1.31 mu g/mL at 200 mg, and 5.61 +/- 2.48 mu g/mL at 400 mg. AUC(0-t) was 19.29 +/- 8.88 mu g center dot h/mL at 100 mg, 34.72 +/- 16.53 mu g center dot h/mL at 200 mg, and 68.00 +/- 28.51 mu g center dot h/mL at 400 mg. PK parameters for adolescents receiving viloxazine ER were also determined. C-max was 2.06 +/- 0.90 mu g/mL at 200 mg, 4.08 +/- 1.67 mu g/mL at 400 mg, and 6.49 +/- 2.87 mu g/mL at 600 mg. AUC(0-t) was 25.78 +/- 11.55 mu g center dot h/mL at 200 mg, 50.80 +/- 19.76 mu g center dot h/mL at 400 mg, and 79.97 +/- 36.91 mu g center dot 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.