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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.

SUBMITTER: Nasser A

PROVIDER: S-EPMC9291887 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:PurposeThe ADHD Rating Scale (ADHD-RS) assesses 18 symptoms of inattention and hyperactivity/impulsivity and has been used in many clinical trials to evaluate the treatment effect of drugs on ADHD. The fifth edition of this scale (ADHD-RS-5) also assesses the impact of inattention and hyperactivity/impulsivity symptoms on six domains of functional impairment (FI): family relationships, peer relationships, completing/returning homework, academic performance at school, controlling behavior at school, and self-esteem. Here, we report the effect of viloxazine extended-release capsules (viloxazine ER), a novel nonstimulant treatment for ADHD in children and adolescents (ages 6-17 years), on FI from a post hoc analysis of four randomized, double-blind, placebo-controlled Phase 3 clinical trials (N=1354).Patients and methodsADHD-RS-5 investigator ratings of ADHD symptoms and FIs were conducted at baseline and weekly post-baseline for 6-8 weeks in the four trials. Change from baseline (CFB) in ADHD-RS-5 FI scores (Total score [sum of 12 FI items] and Inattention and Hyperactivity/Impulsivity subscale scores [sum of 6 corresponding FI items]) and the 30% and 50% Responder Rates (ADHD-RS-5 FI Total score) were compared between viloxazine ER and placebo.ResultsThe reduction (improvement) in ADHD-RS-5 FI scores (Total and subscale scores) and the percentage of responders (30% and 50%) at Week 6 were significantly greater in each viloxazine ER dose group vs placebo. In the 100-400 mg/day viloxazine ER groups, improvements were found as early as Week 1 (100-mg/day) or Week 2 (200-, 400-mg/day) of treatment. Analysis of individual items of ADHD-related FIs demonstrated that the effect of viloxazine ER was observed across all domains of impairment.ConclusionSignificant improvements observed in ADHD-related FIs are consistent with the reduction in inattention and hyperactivity/impulsivity symptoms demonstrated in the viloxazine ER Phase 3 pediatric trials. Therefore, viloxazine ER provides clinically meaningful improvement of ADHD symptoms and functioning in children and adolescents with ADHD, starting as early as Week 1-2 of treatment.

Project description:OBJECTIVE:This was a single-dose, one-period, multicenter, pharmacokinetic (PK) study to evaluate the PK of methylphenidate (MPH) hydrochloride multilayer extended-release capsules (MPH-MLR) in preschool children aged 4 to < 6 years, previously diagnosed with attention-deficit/hyperactivity disorder (ADHD), and on a stable dose of MPH. METHODS:Preschool-aged children (N = 10) received a single oral dose of MPH-MLR (10, 15, or 20 mg) sprinkled over applesauce; a dose equivalent to their pre-enrollment daily dose of MPH. Blood samples for the measurement of MPH concentrations were obtained pre-dose and at 0.5, 1, 2, 3, 4, 6, 8, 10, 12, and 24 h post-dose. No structural model was assumed in the derivation of PK values for analysis. Maximum plasma concentration (Cmax), area under the concentration-time curve (AUC), elimination half-life, clearance (CL), and volume of distribution (Vd) data were compared with a historical group of older children aged 6-11 years (N = 11) and analyzed by bodyweight. Safety (adverse event monitoring, vital signs, electrocardiogram, clinical laboratory testing, physical examination) was assessed. RESULTS:Mean dose-normalized Cmax and area under the curve to the last measurable observation (AUC0-t) values were similar across dose groups, ranging from 0.67 ng/mL/mg (MPH 15 mg) to 0.81 ng/mL/mg (MPH 10 mg) for Cmax/dose, and from 7.80 h × ng/mL/mg (MPH 20 mg) to 8.92 h × ng/mL/mg (MPH 10 mg) for AUC0-t/dose. PK results were integrated into a previously described pharmacostatistical population PK model. Visual predictive check plots showed greater variability in the 6- to 11-year-old group than the 4- to < 6-year-old group, and CL increased with increasing body weight in a greater than dose-proportional manner. Mean CL, normalized for body weight, was constant for all dose groups, ranging from 4.88 L/h/kg to 5.80 L/h/kg. Median time to Cmax ranged from 2.00 to 3.00 h post-dose, and overall, dose-normalized Cmax concentrations indicated greater systemic exposures of MPH-MLR in preschool children aged 4 to < 6 years compared with children aged 6-11 years. Children aged 4 to < 6 years had a lower Vd than children aged 6-11 years. There were no unexpected safety signals. CONCLUSION:The PK of MPH-MLR in preschool children demonstrated the biphasic absorption profile described earlier in older children, and the PK profile in children with ADHD aged 4 to < 6 years was similar to the profile in those aged 6-11 years, apart from a lower Vd and relatively higher systemic MPH levels for children in the preschool group. TRIAL REGISTRATION:Clinicaltrials.gov Identifier: NCT02470234.

Project description:BackgroundViloxazine extended-release is a novel nonstimulant under investigation as a potential treatment for attention-deficit/hyperactivity disorder (ADHD). Given the potential for viloxazine extended-release to be co-administered with stimulant ADHD pharmacotherapies, this trial investigated the pharmacokinetics and safety of combination viloxazine extended-release + lisdexamfetamine dimesylate (lisdexamfetamine) versus viloxazine extended-release and lisdexamfetamine alone.MethodsIn this single-center, cross-over, open-label trial, healthy, non-ADHD adults received single oral doses of 700 mg viloxazine extended-release alone, 50 mg lisdexamfetamine alone, and a combination of viloxazine extended-release (700 mg) + lisdexamfetamine (50 mg), with blood samples collected over 4 days postadministration. The active drug in viloxazine extended-release (viloxazine) and primary metabolite of lisdexamfetamine (d-amphetamine) were measured using chromatographic tandem mass spectrometry. Safety assessments included adverse events, vital signs, echocardiograms, and clinical laboratory evaluations.ResultsThirty-six adults were enrolled, and 34 completed the trial. The least squares geometric mean ratios are reported as [combination / single drug (90% confidence intervals)]. Viloxazine extended-release: Cmax = 95.96% (91.33-100.82), area under the concentration-time curve from 0 to the last measurable time (AUC0-t) = 99.19% (96.53-101.91), and area under the concentration-time curve from 0 to infinity (AUCinf) = 99.23% (96.61-101.93). Lisdexamfetamine: Cmax = 112.78% (109.93-115.71), AUC0-t = 109.64% (105.25-114.22), and AUCinf = 109.52% (105.19-114.03). All reported adverse events, except 1 (moderate vomiting), were mild in severity.ConclusionsCo-administration of viloxazine extended-release and lisdexamfetamine did not impact the pharmacokinetics of viloxazine or d-amphetamine relative to administration of either drug alone. After single dose administration, the combination appeared to be safe and well tolerated.

Project description:Background and objectivesViloxazine 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.MethodsIn 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.ResultsOf 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 (Cmax) = 100.98% (96.21-105.99), area under the concentration-time curve from time zero to the last measurable time (AUCt) = 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, Cmax = 103.55% (97.42-110.07), AUCt = 106.67% (101.01-112.64), and AUC∞ = 106.61% (100.99-112.54). All reported AEs were mild in severity.ConclusionsCoadministration 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.

Project description:Evening-dosed HLD200 is a delayed-release and extended-release methylphenidate (DR/ER-MPH) formulation consisting of uniform, dual-layered microbeads with an inner drug-loaded core. DR/ER-MPH is designed to delay the initial release of drug by 8-10 hours, and thereafter, provide a controlled, extended drug release to target onset of effect upon awakening that lasts into the evening. This phase 3 study evaluated the safety and efficacy of DR/ER-MPH on symptoms and temporal at-home functional impairment in children with attention-deficit/hyperactivity disorder (ADHD).This 3-week, randomized, double-blind, multicenter, placebo-controlled, parallel-group, forced-dose titration trial evaluated DR/ER-MPH (40-80?mg/day) in children aged 6-12 years with ADHD. Primary efficacy endpoint was the ADHD rating scale-IV (ADHD-RS-IV), and the key secondary endpoints were the Before-School Functioning Questionnaire (BSFQ), and Parent Rating of Evening and Morning Behavior-Revised, morning (PREMB-R AM) and evening (PREMB-R PM). Safety measures included spontaneously reported treatment-emergent adverse events (TEAEs) and two TEAEs of special interest, appetite suppression and insomnia (with direct questioning on sleep disturbance).One hundred sixty-one participants were included in the intent-to-treat population (DR/ER-MPH, n?=?81; placebo, n?=?80). After 3 weeks, DR/ER-MPH achieved significant improvements versus placebo in ADHD symptoms (least-squares [LS] mean ADHD-RS-IV: 24.1 vs. 31.2; p?=?0.002), and at-home early morning (LS mean BSFQ: 18.7 vs. 28.4; p?<?0.001; LS mean PREMB-R AM: 2.1 vs. 3.6; p?<?0.001) and late afternoon/evening (LS mean PREMB-R PM: 9.4 vs. 12.2; p?=?0.002) functional impairment. Commonly reported TEAEs (?10%) were insomnia and decreased appetite.DR/ER-MPH was generally well tolerated and demonstrated significant improvements versus placebo in ADHD symptoms and at-home functional impairments in the early morning, late afternoon, and evening in children with ADHD.

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

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