Model-based comparison of subcutaneous versus sublingual apomorphine administration in the treatment of motor fluctuations in Parkinson's disease.

The objective of this study was to compare the effectiveness of subcutaneous (SC) and sublingual (SL) formulations of apomorphine for the treatment of motor fluctuations in Parkinson's disease using a pharmacokinetics (PK)/pharmacodynamics (PD) modeling approach. The PK of SC and SL apomorphine are best described by a one-compartment model with first-order absorption and a two-compartment model with delayed absorption, respectively. The PK/PD model relating apomorphine plasma concentrations to the Unified Parkinson's Disease Rating Scale (UPDRS) motor scores was described by a sigmoidal Emax model assuming effective concentration = drug concentration in an effect compartment. Apomorphine concentrations and UPDRS motor scores were simulated from the PK/PD models using 500 hypothetical subjects. UPDRS motor score change from baseline was evaluated using time to clinically relevant response, response duration, area under the curve, maximal response, and time to maximal response. Higher doses of each apomorphine formulation were associated with shorter time to response, longer response duration, and greater maximal response. Although the mean maximal responses to SC and SL apomorphine were comparable, the time to response was four times shorter (7 vs. 31 min) and time to maximal response was two times shorter (27 vs. 61 min) for 4 mg SC vs. 50 mg SL. Thus, faster onset of action was observed for the SC formulation compared to SL. These data may be useful for physicians when selecting "on demand" therapy for patients with Parkinson's disease experiencing motor fluctuations.

A post hoc analysis of the effect of viloxazine extended-release capsules on learning and school problems in children and adolescents with attention-deficit/hyperactivity disorder.

Improvement in attention-deficit/hyperactivity disorder (ADHD) symptoms vs. placebo was reported in a series of pediatric clinical trials of viloxazine extended-release capsules (viloxazine ER; Qelbree™). This post hoc analysis of those studies evaluated the effect of viloxazine ER on learning and school problems (LSPs). We used data from four Phase 3 placebo-controlled trials of 100-600 mg/day viloxazine ER (N = 1354; 6-17 years of age). LSPs were evaluated using the School domain of the Weiss Functional Impairment Rating Scale-Parent Report (WFIRS-P-S) and the Learning Problems content scale of the Conners 3rd Edition-Parent Short Form (C3PS-LP) at baseline and end of study (≥ Week 6). ADHD symptoms were assessed weekly using the ADHD Rating Scale 5th Edition. The analyses were performed using the general linear mixed model with participant as a random effect. The responder analyses were performed using the Chi-square test. Viloxazine ER demonstrated significantly greater improvements in WFIRS-P-S (p < 0.0001) and C3PS-LP (p = 0.0113) scores vs. placebo. The response rate for the WFIRS-P-S was significantly greater for viloxazine ER vs. placebo (p = 0.001), and the number needed to treat (NNT) was 10.3 (effect size 0.7). Conversely, response rates for C3PS-LP did not differ between groups (p = 0.9069). In addition to ADHD symptoms improvement demonstrated in previous studies, viloxazine ER significantly reduced LSPs in pediatric subjects with ADHD. The responder analyses and NNT estimates indicate that a substantial number of children and adolescents with ADHD treated with viloxazine ER improved in clinically assessed LSPs.

The role of placebo response in the efficacy outcome assessment in viloxazine extended-release pivotal trials in paediatric subjects with attention-deficit/hyperactivity disorder.

AIMS: Four Phase 3 studies evaluated efficacy and safety of viloxazine extended-release in the treatment of attention-deficit/hyperactivity disorder (ADHD). The primary efficacy objective-change from baseline in ADHD Rating Scale-5 (ADHD-RS-5) Total score at end of study (EOS)-was not met in one of the studies (812P304). A band-pass analysis was performed to evaluate the impact of placebo response on the results. METHODS: The distribution of placebo response at EOS of each trial was evaluated. The 2.5th and 97.5th percentiles of the distribution of ADHD-RS-5 Total score were used as boundaries for the band-pass analysis. An independent mixed model for repeated measures analysis was conducted for each trial using all eligible data (active and placebo) from the total and band-pass filtered populations. RESULTS: The 2.5th and 97.5th percentiles at EOS were 3.5 and 53.5, respectively. Application of the band-pass filter (filtering out all subjects [active, n = 305 (32.1%) and placebo, n = 134 (33.5%)] of clinical sites with placebo scores <3.5 or >53.5) revealed statistically significant improvement at the primary endpoint (600-mg/d viloxazine ER vs. placebo) in Study 812P304 (mean [confidence interval] = 4.9537 [0.5405-9.3669]), previously masked by a high placebo response (mean [confidence interval] = 3.5756 [-0.3332-7.4844]). The outcome of the analysis indicated that the impact of the band-pass adjustment is greater when placebo response is higher. CONCLUSION: This analysis indicated that a higher placebo response in Study 812P304 confounded the assessment of treatment effect. Application of the band-pass methodology confirmed the positive results of the 3 prior studies and the signal detection confounder in the fourth study.

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

BACKGROUND: Viloxazine 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. METHODS: In 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. RESULTS: Thirty-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. CONCLUSIONS: Co-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.

A Phase 3, Placebo-Controlled Trial of Once-Daily Viloxazine Extended-Release Capsules in Adolescents With Attention-Deficit/Hyperactivity Disorder.

PURPOSE: This phase 3 clinical trial evaluated the efficacy and safety of viloxazine extended-release capsules (VLX-ER) as a monotherapy for attention-deficit/hyperactivity disorder (ADHD) in adolescents (12-17 years). METHODS: Eligible subjects (n = 310) were randomized to receive once-daily 200 and 400 mg VLX-ER, or placebo for 6 weeks. The primary efficacy end point was change from baseline (CFB) at the end of study (EOS) in ADHD Rating Scale-5 Total score. Key secondary end points were Clinical Global Impression-Improvement score at EOS, CFB at EOS in Conners 3-Parent Short Form Composite T-score, and CFB at EOS in Weiss Functional Impairment Rating Scale-Parent Total average score. RESULTS: In the 200-mg/d and 400-mg/d VLX-ER treatment groups, a significant improvement was found in the CFB at EOS in ADHD Rating Scale-5 Total (P = 0.0232, P = 0.0091) and Inattention (P = 0.0424, P = 0.0390) and Hyperactivity/Impulsivity (P = 0.0069, P = 0.0005) subscale scores versus placebo. The Clinical Global Impression-Improvement score was significantly improved at EOS in the 200-mg/d and 400-mg/d VLX-ER groups versus placebo (P = 0.0042, P = 0.0003). The Conners 3-Parent Short Form composite T-score and Weiss Functional Impairment Rating Scale-Parent Total average score exhibited improvement in both VLX-ER groups; however, the difference versus placebo was not statistically significant. The most common treatment-related adverse events were somnolence, headache, decreased appetite, nausea, and fatigue. The adverse event-related discontinuation rates were <5% in all groups. CONCLUSIONS: Viloxazine extended-release demonstrated statistically significant and clinically meaningful improvement in ADHD symptoms in adolescents and was generally well tolerated.

Closing the gap: unmet needs of individuals with impulsive aggressive behavior observed in children and adolescents.

Impulsive aggressive (IA, or impulsive aggression) behavior describes an aggregate set of maladaptive, aggressive behaviors occurring across multiple neuropsychiatric disorders. IA is reactive, eruptive, sudden, and unplanned; it provides information about the severity, but not the nature, of its associated primary disorder. IA in children and adolescents is of serious clinical concern for patients, families, and physicians, given the detrimental impact pediatric IA can have on development. Currently, the ability to properly identify, monitor, and treat IA behavior across clinical populations is hindered by two major roadblocks: (1) the lack of an assessment tool designed for and sensitive to the set of behaviors comprising IA, and (2) the absence of a treatment indicated for IA symptomatology. In this review, we discuss the clinical gaps in the approach to monitoring and treating IA behavior, and highlight emerging solutions that may improve clinical outcomes in patients with IA.

Evaluating the likelihood to be helped or harmed after treatment with viloxazine extended-release in children and adolescents with attention-deficit/hyperactivity disorder.

AIMS: When clinicians evaluate potential medications for their patients, they must weigh the probability of a treatment's benefits against the possible risks. To this end, the present analyses evaluate the novel nonstimulant viloxazine extended-release (viloxazine ER) using measures of effect size to describe the potential benefits of its treatment in children and adolescents with attention-deficit/hyperactivity disorder (ADHD) as well as the risk of discontinuation because of intolerable adverse events. METHODS: These post hoc analyses use pooled data from four pivotal Phase 3 trials in paediatric patients treated with viloxazine ER. The Likelihood to be Helped or Harmed (LHH) effect size measure was calculated to describe the probability of patients benefiting from treatment vs discontinuing. The Number Needed to Treat (NNT) was calculated from frequently used thresholds of response. The Number Needed to Harm (NNH) was calculated using discontinuations because of adverse events. RESULTS: LHH values for viloxazine ER ranged from 5 to 13, suggesting that subjects were 5-13 times more likely to benefit from, rather than discontinue, viloxazine ER treatment. Specifically, NNT values for viloxazine ER treatment ranged from 6 to 7. NNH values for viloxazine ER treatment ranged from 31 to 74. By convention, single-digit NNTs (<10) suggest the intervention is potentially useful, while NNH values ≥10 for adverse events suggest it is potentially safe or tolerable. CONCLUSIONS: These results indicate that patients with ADHD are likely to benefit from treatment with viloxazine ER, and are unlikely to discontinue, as viloxazine ER treatment was associated with favourable LHH, NNT, and NNH values. Clinicaltrials.gov: NCT03247530, NCT03247543, NCT03247517, NCT03247556.

Efficacy, Safety, and Tolerability of RBP-7000 Once-Monthly Risperidone for the Treatment of Acute Schizophrenia: An 8-Week, Randomized, Double-Blind, Placebo-Controlled, Multicenter Phase 3 Study.

RBP-7000 is a sustained-release formulation of risperidone for the treatment of schizophrenia, designed to be administered by once-monthly subcutaneous injection using the ATRIGEL delivery system. This study assessed the efficacy, safety, and tolerability of RBP-7000 compared with placebo in subjects with acute exacerbation of schizophrenia. Inpatients were randomly assigned to 8 weeks of double-blind treatment with subcutaneous 90 or 120 mg of RBP-7000 or placebo. Efficacy was evaluated using a mixed-model repeated-measures analysis of the change from baseline (the last nonmissing value before the first dose of RBP-7000 or placebo on day 1) to end of the study in Positive and Negative Syndrome Scale (PANSS) total score (primary efficacy measure) and Clinical Global Impression-Severity score (secondary efficacy measure). The least-squares means from the repeated-measures analysis for the change from baseline in the PANSS total scores for placebo was -9.219 (SE, 1.2162). RBP-7000 produced statistically and clinically significant differences in mean reductions from baseline in PANSS total scores (90-mg RBP-7000 compared with placebo, -6.148 [-9.982 to -2.314], P = 0.0004; 120-mg RBP-7000 compared with placebo, -7.237 [-11.045 to -3.429], P < 0.0001) and significantly improved Clinical Global Impression-Severity scores (90-mg RBP-7000 compared with placebo, -0.350 [-0.557 to -0.143], P = 0.0002; 120-mg RBP-7000 compared with placebo, -0.396 [-0.602 to -0.190], P < 0.0001). Both RBP-7000 dosages were generally well tolerated. The most frequently reported treatment-emergent adverse events in RBP-7000 groups compared with placebo were somnolence, weight gain, and akathisia. The overall incidence of extrapyramidal syndrome-related effects was low and similar across groups. RBP-7000 may provide a new, long-acting alternative treatment for use in adults with acute schizophrenia.

Sustained-Release Buprenorphine (RBP-6000) Blocks the Effects of Opioid Challenge With Hydromorphone in Subjects With Opioid Use Disorder.

A major goal for the treatment of opioid use disorder is to reduce or eliminate the use of illicit opioids. Buprenorphine, a µ-opioid receptor partial agonist and kappa opioid receptor antagonist, is now being developed as a monthly, sustained-release formulation (RBP-6000). The objective of this study was to demonstrate that RBP-6000 blocks the subjective effects and reinforcing efficacy of the µ-opioid receptor agonist hydromorphone (intramuscularly administered) in subjects with moderate or severe opioid use disorder. Subjects were first inducted and dose stabilized on sublingual buprenorphine/naloxone (8-24 mg daily; dose expressed as the buprenorphine component), then received two subcutaneous injections of RBP-6000 (300 mg) on Day 1 and Day 29. Hydromorphone challenges (6 mg, 18 mg or placebo administered in randomized order) occurred on 3 consecutive days of each study week before and after receiving RBP-6000. Subjects reported their responses to each challenge on various 100-mm Visual Analogue Scales (VAS). Subjects also completed a choice task to assess the reinforcing efficacy of each hydromorphone dose relative to money. At baseline, mean "drug liking" VAS scores for hydromorphone 18 mg and 6 mg versus placebo were 61 mm (95% confidence interval, 52.3-68.9) and 45 mm (95% confidence interval, 37.2-53.6), respectively. After 300 mg RBP-6000 was administered, mean VAS score differences from placebo were less than 10 mm through week 12. The reinforcing efficacy of hydromorphone decreased in a parallel manner. This study demonstrated that RBP-6000 at a 300 mg dose provides durable and potent blockade of the subjective effects and reinforcing efficacy of hydromorphone in subjects with moderate or severe opioid use disorder.

Impact of Viloxazine Extended-Release Capsules (Qelbree®) on Select Cytochrome P450 Enzyme Activity and Evaluation of CYP2D6 Genetic Polymorphisms on Viloxazine Pharmacokinetics.

BACKGROUND AND OBJECTIVE: Viloxazine extended-release (ER) [Qelbree®] is a nonstimulant attention-deficit/hyperactivity disorder (ADHD) treatment. In vitro studies suggested potential for viloxazine to inhibit cytochrome 450 (CYP) enzymes 1A2, 2B6, 2D6 and 3A4. This clinical study therefore evaluated viloxazine ER effects on index substrates for CYP1A2, 2D6, and 3A4, and secondarily evaluated the impact of CYP2D6 polymorphisms on viloxazine pharmacokinetics. METHODS: Thirty-seven healthy subjects received a modified Cooperstown cocktail (MCC; caffeine 200 mg, dextromethorphan 30 mg, midazolam 0.025 mg/kg) on Day 1, viloxazine ER 900 mg/day on Days 3-5, and a combination of viloxazine ER 900 mg and MCC on Day 6. Viloxazine ER effects on MCC substrates were evaluated using analysis of variance. The impact of CYP2D6 genetic polymorphisms on steady-state viloxazine plasma concentrations was evaluated using Student's t test assessing pharmacokinetic parameter differences between poor versus extensive metabolizers. RESULTS: The least squares geometric mean ratio [GMR%] (90% CI) of MCC substrate + viloxazine ER/MCC substrate alone for caffeine maximum concentration (Cmax), area under the plasma concentration-time curve from time 0 to the last quantifiable concentration (AUCt), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC∞) was 99.11 (95.84-102.49), 436.15 (398.87-476.92), and 583.35 (262.41-1296.80), respectively; 150.76 (126.03-180.35), 185.76 (155.01-222.61), and 189.71 (160.37-224.42) for dextromethorphan Cmax, AUCt, and AUC∞, respectively; and 112.81 (104.71-121.54), 167.56 (153.05-183.45), and 168.91 (154.38-184.80) for midazolam Cmax, AUCt, and AUC∞, respectively. At steady state, viloxazine least squares GMR (90% CI) for poor/extensive CYP2D6 metabolizers were Cmax 120.70 (102.33-142.37) and area under the plasme concentration-time curve from time 0 to 24 hours (AUC0-24 125.66 (105.36-149.87)). CONCLUSION: Viloxazine ER is a strong CYP1A2 inhibitor and a weak CYP2D6 and CYP3A4 inhibitor. CYP2D6 polymorphisms did not meaningfully alter the viloxazine ER pharmacokinetic profile.

Advanced Model-based Approach to Evaluate Human Plasma, Cerebrospinal Fluid, and Neuronal mTORC1 Activation Biomarkers After NV-5138 Administration in Healthy Volunteers.

PURPOSE: NV-5138 ([S]-2-amino-5,5-difluoro-4,4-dimethylpentanoic acid) is an orally bioavailable, small-molecule activator of the mechanistic target of rapamycin complex 1 (mTORC1) pathway in development for treatment-resistant depression. The authors established a model to describe the relationship between plasma and cerebrospinal fluid (CSF) concentrations of NV-5138 and between CSF concentrations and potential biomarkers thought to be associated with mTORC1 activity (ie, orotic acid, N-acetylmethionine, and N-formylmethionine). METHODS: Data were collected from a randomized, double-blind, placebo-controlled, tolerability, and pharmacokinetic (PK) parameter study of 5 ascending (400, 800, 1600, 2400, and 3000 mg), once-daily oral doses of NV-5138 in healthy subjects. NV-5138 plasma PK parameter samples were collected at 15 time points over 24 hours on days 1 and 7, and at pre dose on days 2-6 for all doses. NV-5138 CSF PK parameter and CSF biomarker samples were collected on days 1 and 7 at pre dose and 4, 8, and 12 hours post dose for all doses except 3000 mg. A model-based approach was used to develop and validate a model that describes the relationship between NV-5138 in CSF and biomarker concentrations. FINDINGS: Twenty-four of the 42 enrolled subjects had simultaneous plasma and CSF measurements of NV-5138 and CSF biomarker concentrations and were included in the PK parameter and pharmacodynamic (PD) analyses. A 2-compartment plasma and CSF PK parameter, with indirect PD effects, model was developed and validated. NV-5138 plasma concentrations were positively correlated with those in CSF, although CSF concentrations lagged slightly behind those in plasma, as indicated by a counterclockwise hysteresis effect. Similarly, the relationship between the PD measures of mTORC1 activation and NV-5138 was also characterized by counterclockwise hysteresis, when the increase in CSF biomarker concentrations lagged behind those of NV-5138, consistent with a signaling intermediary/cascade, such as mTORC1. Maximal biomarker activation was achieved at NV-5138 CSF concentrations of approximately 3 µg/mL, which were associated with daily doses of 1600 mg NV-5138. The safety profile analysis (n = 42) found that most of the reported adverse events were mild in severity, with no severe, serious, unusual, or unexpected adverse events or any dissociative effects; 2 subjects (400-mg cohort) discontinued due to adverse events that were judged to be unrelated to study medication. IMPLICATIONS: The model will be used for designing future efficacy and tolerability studies. Consecutive daily doses of NV-5138 were well tolerated in this healthy volunteer study.

Response of peer relations and social activities to treatment with viloxazine extended-release capsules (Qelbree® ): A post hoc analysis of four randomized clinical trials of children and adolescents with attention-deficit/hyperactivity disorder.

INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is associated with impairments related to peer relations (PR) and social activities (SA). The objective of this post hoc analysis was to assess the degree to which viloxazine extended-release (viloxazine ER; viloxazine extended-release capsules; Qelbree® ) improves clinical assessments of PR and SA in children and adolescents with ADHD. METHODS: Data were used from four Phase III placebo-controlled trials of 100 to 600 mg/day of viloxazine ER (N = 1354; 6-17 years of age). PR and SA were measured with the Peer Relations content scale of the Conners 3rd Edition Parent Short Form's Peer Relation content scale (C3PS-PR) and the Social Activities domain of the Weiss Functional Impairment Rating Scale-Parent Report's (WFIRS-P-SA) at baseline and end of study. ADHD symptoms were assessed weekly with the ADHD Rating Scale, 5th Edition. The analyses relied on the general linear mixed model with the subject as a random effect. RESULTS: Improvement in C3PS-PR (p = .0035) and WFIRS-P-SA (p = .0029) scores were significantly greater in subjects treated with viloxazine ER compared with placebo. When using measures of clinically meaningful response, the C3PS-PR responder rate was significantly higher for viloxazine ER (19.2%) compared with placebo (14.1%) and the difference was statistically significant (p = .0311); the Number Needed to Treat (NNT) was 19.6. The WFIRS-P-SA responder rate was significantly higher for viloxazine ER (43.2%) compared with placebo (28.5%) and the difference was statistically significant (p < .0001); the NNT was 6.8. The standardized mean difference effect size for both PR and SA was 0.09. CONCLUSIONS: Viloxazine ER significantly reduces the impairment of PR and SA in children and adolescents with ADHD. Although its effects on PR and SA are modest, many ADHD patients can be expected to achieve clinically meaningful improvements in PR and SA with viloxazine ER treatment for longer than 6 weeks.

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

BACKGROUND AND OBJECTIVES: Viloxazine extended-release (viloxazine ER) capsules (QelbreeTM) is a novel nonstimulant recently approved as a treatment for attention-deficit/hyperactivity disorder in children and adolescents. Here, we determined whether the pharmacokinetics of viloxazine are impacted by consuming the capsule contents sprinkled on applesauce rather than an intact capsule, and the effect of a high-fat meal on the pharmacokinetics of viloxazine ER. METHODS: This was a randomized, open-label, crossover, three-treatment, three-period study in healthy adults using orally administered single-dose viloxazine ER 200 mg capsules. Subjects consumed: (1) an intact capsule after a 10-h fast (control condition); (2) the capsule contents sprinkled on one tablespoon of applesauce; and (3) an intact capsule with a standard high-fat meal. Blood samples were collected for 48 h post-dosing. Relative bioavailability analyses were performed to assess the impact of each test condition against the control condition (intact capsule, fasting). The absence of an impact was indicated if the 90% confidence interval (CI) for the least-squares geometric mean ratio (LSGMR) of maximal concentration (Cmax), the area under the concentration-time curve from time 0 to the last measurable concentration time (AUClast), and the area under the concentration-time curve from time 0 to infinity (AUCinf) were within the predetermined no-difference limits of 80-125%. RESULTS: Out of 27 enrolled subjects, 25 were included in the pharmacokinetic analysis. The LSGMR (90% CI) for viloxazine ER sprinkled vs. intact were 90.10% (83.35-97.40) for Cmax, 93.71% (89.09-98.57) for AUClast, and 95.37% (89.80-101.28) for AUCinf. The LSGMR (90% CI) for viloxazine ER consumed in the fed state vs. fasting state were 90.86% (84.05-98.21) for Cmax, 89.68% (85.26-94.33) for AUClast, and 92.35% (86.96-98.07) for AUCinf. The 90% CIs of the LSGMRs were within the predetermined no-difference limits of 80-125%. Viloxazine ER was well tolerated, with most adverse events reported as mild. CONCLUSIONS: These data suggest that viloxazine ER can be consumed sprinkled on applesauce or as intact capsules with or without meals without significantly changing its pharmacokinetics.

Predicting efficacy of viloxazine extended-release treatment in adults with ADHD using an early change in ADHD symptoms: Machine learning Post Hoc analysis of a phase 3 clinical trial.

Early response to viloxazine extended-release (viloxazine ER, Qelbree®) treatment predicted efficacy outcome in pediatric subjects with attention-deficit/hyperactivity disorder (ADHD). This study sought to determine whether the machine learning lasso model used in the pediatric study would predict response to viloxazine ER in an adult population based on early improvements in ADHD symptoms. We used data from a double-blind, placebo-controlled, flexible-dose (200-600 mg) study of viloxazine ER (N = 354; 18 to 60 years old). Area under the Receiver Operating Characteristic Curve (ROC AUC) statistics were computed using the lasso model from pediatric data to predict responder status in adults. Response was defined as ≥50% reduction from baseline in the Adult ADHD Investigator Symptoms Rating Scale (AISRS) Total score at Week 6. The adult study sample included 127 viloxazine ER-treated subjects with Week 6 data. Fifty-one subjects (40.2%) were categorized as responders. The ROC curves indicated that data collected up to Week 2 were sufficient to accurately predict treatment response at Week 6 with 68% positive predictive power, 80% sensitivity, and 74% specificity. This analysis demonstrated that the predictive model estimated from the child data generalizes to adults with ADHD, further supporting the consistency of viloxazine ER treatment across age groups.

A Phase III, Randomized, Double-Blind, Placebo-Controlled Trial Assessing the Efficacy and Safety of Viloxazine Extended-Release Capsules in Adults with Attention-Deficit/Hyperactivity Disorder.

BACKGROUND AND OBJECTIVE: Attention-deficit/hyperactivity disorder is a neurodevelopmental disorder that typically begins in childhood and often persists into adulthood. Recent phase III trials have demonstrated the efficacy and safety of viloxazine extended-release capsules (viloxazine ER; Qelbree®) in pediatrics (6-17 years of age). The aim of this study was to evaluate the efficacy and safety of viloxazine ER in adults with attention-deficit/hyperactivity disorder. METHODS: This was a phase III, randomized, double-blind, placebo-controlled, two-arm trial in adults (18-65 years of age) with attention-deficit/hyperactivity disorder. Eligible subjects were randomized 1:1 to viloxazine ER (flexible dose of 200-600 mg/day) or matched placebo. The primary efficacy endpoint was the change from baseline at end of study (week 6) in the Adult ADHD Investigator Symptom Rating Scale (AISRS) total score. The key secondary endpoint was the change from baseline at end of study in the Clinical Global Impressions-Severity of Illness (CGI-S) score. Additional secondary outcome measures included the AISRS Inattention and Hyperactivity/Impulsivity subscales, the Behavior Rating Inventory of Executive Function-Adult (BRIEF-A), the Generalized Anxiety Disorder-7 Item (GAD-7), and the Clinical Global Impressions-Improvement (CGI-I); each was analyzed at end of study. Responder rates on CGI scales and the AISRS were also assessed. RESULTS: A total of 374 subjects were randomized. At end of study, the mean viloxazine ER dose was 504 mg. The reduction in the change from baseline at end of study AISRS total score (least-square means ± standard error) was significantly greater in subjects treated with viloxazine ER (-15.5 ± 0.91) compared with placebo (-11.7 ± 0.90), p = 0.0040. The reduction in the CGI-S score was also significantly greater in subjects treated with viloxazine ER (-1.4 ± 0.10) compared with placebo (-1.0 ± 0.10), p = 0.0023. The viloxazine ER group demonstrated significantly greater improvements in the AISRS Inattention (p = 0.0015) and Hyperactivity/Impulsivity (p = 0.0380) subscales, the CGI-I (p = 0.0076), and the BRIEF-A Global Executive Composite (p = 0.0468) and Metacognition Index (p = 0.0100). Analysis of categorical secondary endpoints revealed that the viloxazine ER group had a significantly higher AISRS 30% response rate compared with placebo (p = 0.0395); all other comparisons were not significant. Many treatment effects (including the primary and key secondary endpoints) were significant by week 2. The most common treatment-related adverse events that occurred in ≥5% of subjects receiving viloxazine ER were insomnia (14.8%), fatigue (11.6%), nausea (10.1%), decreased appetite (10.1%), dry mouth (9.0%), and headache (9.0%). Viloxazine ER was well tolerated, with a 9.0% discontinuation rate due to adverse events compared with 4.9% in the placebo group. CONCLUSIONS: Treatment with viloxazine ER resulted in a statistically significant improvement in primary and key secondary endpoints, indicating improvements in attention-deficit/hyperactivity disorder symptomology, executive function, and overall clinical illness severity in adults. Viloxazine ER was well tolerated at the tested doses in adults with attention-deficit/hyperactivity disorder. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04016779.

Attention-deficit/hyperactivity disorder (ADHD) is a condition characterized by inattention (difficulty maintaining focus), and/or impulsiveness/hyperactivity. In 2021, a nonstimulant medication called viloxazine ER (brand name: Qelbree^®) received US FDA-approval for ADHD in children and adolescents (aged 6 to 17 years), based on efficacy and safety demonstrated in clinical trials. Here we present results of a phase 3, randomized, double-blind, placebo-controlled, clinical trial that enrolled 374 adults with ADHD. In this trial, half the patients received viloxazine ER, and half received placebo (identical capsule without active ingredient). Medication doses ranged from 200­600 mg/day, based on symptom response and presence of side effects. To reduce bias, patients and investigators did not know which medication the patient was receiving. The primary measure of efficacy was the Adult ADHD Investigator Symptom Rating Scale (AISRS), a standardized questionnaire rating presence and severity of patient-reported ADHD symptoms. At the end of the 6-week trial, participants receiving viloxazine ER showed greater improvement in ADHD symptoms according to AISRS than those receiving placebo. Improvement was seen in both the Inattentive and Impulsive/Hyperactive components of ADHD and in other study measures, including a measure of behaviors called Executive Function. Viloxazine ER was generally safe and well-tolerated in the trial. The most common side effects were insomnia (14.8%), fatigue (11.6%), and nausea (10.1%). Overall, 9.0% of patients receiving viloxazine and 5% receiving placebo left the trial because of side effects. Due to these positive results, the US FDA recently approved viloxazine ER to treat adults with ADHD.

Early response to SPN-812 (viloxazine extended-release) can predict efficacy outcome in pediatric subjects with ADHD: a machine learning post-hoc analysis of four randomized clinical trials.

Machine learning (ML) was used to determine whether early response can predict efficacy outcome in pediatric subjects with ADHD treated with SPN-812. We used data from four Phase 3 placebo-controlled trials of 100- to 600-mg/day SPN-812 (N=1397; 6-17 years of age). The treatment response was defined as having a ≥50% reduction in change from baseline (CFB) in ADHD Rating Scale-5 (ADHD-RS-5) Total score at Week 6. The variables used were: ADHD-RS-5 Total score, age, body weight, and body mass index at baseline; CFB ADHD-RS-5 Total score at Week 1, cumulative change in ADHD-RS-5 Total score at Week 2, and cumulative change in ADHD-RS-5 Total score at Week 3; Clinical Global Impressions-Improvement (CGI-I) score at Week 1, 2, and 3; and target dose. Using the best selected model, lasso regression, to generate importance scores, we found that change in ADHD-RS-5 Total score and CGI-I score were the best predictors of efficacy outcome. Change in ADHD-RS-5 Total score at Week 2 could predict treatment response at Week 6 (75% positive predictive power, 75% sensitivity, 74% specificity). Therefore, early response after two weeks of treatment with once-daily SPN-812 in pediatric patients with ADHD can predict efficacy outcome at Week 6.

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

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 (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. 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.

A Double-Blind, Randomized Study of Extended-Release Molindone for Impulsive Aggression in ADHD.

Objective: To evaluate efficacy and safety of SPN-810 (extended-release molindone) in a Phase-2b, randomized, double-blind, placebo-controlled, dose-ranging study of children (6-12 years) with ADHD and persistent impulsive aggression (IA). Method: After lead-in, children were randomized to (a) placebo (N = 31); (b) low-dose (N = 29, 12/18 mg/day); (c) medium-dose (N = 30, 24/36 mg/day); and (4) high-dose (N = 31, 36/54 mg/day) groups. Treatment included ~2.5-week titration, 3-week maintenance, and 1-week tapering/conversion, alongside existing monotherapy (stimulants/nonstimulants) and behavioral therapy. The primary endpoint was change in Retrospective-Modified Overt Aggression Scale (R-MOAS) score at end of study, with safety monitored. Results: A total of 95 (78.5%) children completed the study. Aggression (R-MOAS) improved with low and medium doses (low dose: p = .031; medium dose: p = .024; high dose: p = .740). The most common adverse events were headache (10.0%), sedation (8.9%), and increased appetite (7.8%). Conclusion: These results suggest SPN-810 may be effective in reducing residual IA behaviors in children with ADHD. Research is still needed to support the benefit-risk profile of SPN-810 in pediatric populations.

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. Cmax 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. AUC0-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. Cmax 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. AUC0-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.