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.

Convolution-based approach for modeling the paliperidone extended release and Long-Acting Injectable (LAI) PK of once-, and three-monthly products administration and for optimizing the development of new LAI products.

The aim of this paper was to develop a convolution-based modeling approach for describing the paliperidone PK resulting from the administration of extended-release once-a-day oral dose, and once- and three monthly long-acting injectable products and to compare the performances of this approach to the traditional modeling strategy. The results of the analyses indicated that the traditional and convolution-based models showed comparable performances in the characterization of the paliperidone PK. However, the convolution-based approach showed several appealing features that justify the choice of this modeling as a preferred tool for modeling Long Acting Injectable (LAI) products and for deploying an effective model-informed drug development process. In particular, the convolution-based modeling can (a) facilitate the development of in vitro/in vivo correlation, (b) be used to identify formulations with optimal in vivo release properties, and (c) be used for optimizing the clinical benefit of a treatment by supporting the implementation of integrated models connecting in vitro and in vivo drug release, in vivo drug release to PK, and PK to PD and biomarker endpoints. A case study was presented to illustrate the benefits and the flexibility of the convolution-based modeling outcomes. The model was used to evaluate the in vivo drug release properties associated with a hypothetical once-a-year administration of a LAI product with the assumption that the expected paliperidone exposure during a 3-year treatment overlays the exposure expected after repeated administrations of a 3-month LAI product.

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.

Model-Based Approach for Establishing the Predicted Clinical Response of a Delayed-Release and Extended-Release Methylphenidate for the Treatment of Attention-Deficit/Hyperactivity Disorder.

PURPOSE/BACKGROUND: HLD200 is an evening-dosed, delayed-release and extended-release methylphenidate (DR/ER-MPH) that provides a consistent delay in initial drug release to target onset of therapeutic effect from awakening and maintain it into the evening. Building on a modeling framework established with other extended-release methylphenidate formulations, pharmacokinetic (PK) and PK/pharmacodynamic (PD) models for DR/ER-MPH were developed to describe the time course of effect in response to a range of doses and administration times. METHODS/PROCEDURES: Using available PK data from healthy adults, a population PK model was developed using a 1-compartment model with a time-varying absorption rate described by a single Weibull function. A PK/PD model was then developed using Swanson, Kotkin, Agler, M-Flynn, and Pelham combined scores from a phase 3 trial of children with attention-deficit/hyperactivity disorder and simulated plasma concentration-time data. Simulations using the PK/PD model were performed for doses of 60, 80, and 100 mg of DR/ER-MPH, administered 4 to 14 hours before the classroom day. FINDINGS/RESULTS: The PK/PD model predicts that DR/ER-MPH produces a clinical response from early morning into the late afternoon or evening, with increased duration of response occurring with increasing doses. Furthermore, the PK/PD model predicts that maximal clinical effect is achieved with DR/ER-MPH administered 12 hours before the start of the classroom day. IMPLICATIONS/CONCLUSIONS: Model-predicted duration of benefit with DR/ER-MPH is consistent with trial data documenting improvements in functional impairment during the early morning and evening. This model may facilitate dosage optimization by predicting changes in clinical benefit with dose and administration time adjustment.

Model based approach for estimating the dosage regimen of indomethacin a potential antiviral treatment of patients infected with SARS CoV-2.

To face SARS-CoV-2 pandemic various attempts are made to identify potential effective treatments by repurposing available drugs. Among them, indomethacin, an anti-inflammatory drug, was shown to have potent in-vitro antiviral properties on human SARS-CoV-1, canine CCoV, and more recently on human SARS-CoV-2 at low micromolar range. Our objective was to show that indomethacin could be considered as a promising candidate for the treatment of SARS-CoV-2 and to provide criteria for comparing benefits of alternative dosage regimens using a model-based approach. A multi-stage model-based approach was developed to characterize % of recovery and viral load in CCoV-infected dogs, to estimate the PK of indomethacin in dog and human using published data after administration of immediate (IR) and sustained-release (SR) formulations, and to estimate the expected antiviral activity as a function of different assumptions on the effective exposure in human. Different dosage regimens were evaluated for IR formulation (25 mg and 50 mg three-times-a-day, and 25 mg four-times-a-day), and SR formulation (75 mg once and twice-a-day). The best performing dosing regimens were: 50 mg three-times-a-day for the IR formulation, and 75 mg twice-a-day for the SR formulation. The treatment with the SR formulation at the dose of 75 mg twice-a-day is expected to achieve a complete response in three days for the treatment in patients infected by the SARS-CoV-2 coronavirus. These results suggest that indomethacin could be considered as a promising candidate for the treatment of SARS-CoV-2 whose potential therapeutic effect need to be further assessed in a prospective clinical trial.

Safety, tolerability, pharmacokinetics and pharmacokinetic-pharmacodynamic modelling of the novel H4 receptor inhibitor SENS-111 using a modified caloric test in healthy subjects.

AIM: A Phase 1 study was performed to evaluate safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the selective histamine H4 receptor antagonist SENS-111, an oral small molecule. METHODS: One hundred healthy subjects were randomized in a placebo-controlled, double-blind study evaluating single-ascending doses (SAD; 100-500 mg) and multiple-ascending doses (MAD; 50-150 mg day-1 , 4 days; 200-250 mg day-1 , 7 days). Effects of SENS-111 on nystagmus and vertigo induced by modified caloric tests were measured in the MAD studies. Population PK and PK/PD models were developed using a nonlinear mixed-effects approach. RESULTS: SENS-111 was well tolerated with mild to moderate events. No sedation was reported. A maximal tolerated dose was not reached. Dose-proportional increases in concentrations were seen up to 200 mg and more than dose-proportional thereafter, with mean half-life between 24 and 56 h. The caloric test induced mild but measurable vertigo and nystagmus with large intra/inter-individual variation for all parameters. SENS-111 did not significantly impact nystagmus but significantly improved latency of vertigo appearance/disappearance, duration and European Evaluation of Vertigo questionnaire parameters vs. baseline. A two-compartment model with first-order absorption, distribution and elimination best fit the data. PK/PD indirect modelling applied to vertigo duration and latency of appearance indicated maximum activity between 100 and 500 ng ml-1 plasma concentrations, corresponding to 100 and 200 mg day-1 , which are appropriate for clinical efficacy evaluations in vestibular diseases. CONCLUSIONS: SENS-111 is a well-tolerated first-in-class H4 receptor antagonist with acceptable PK for oral daily dosing. PK/PD modelling determined plasma concentrations and doses for efficacy studies in patients with vertigo symptoms.

Continuous-time Markov modelling of flexible-dose depression trials.

The aim of this paper is to provide a systematic methodology for modelling longitudinal data to be used in contexts of limited or even absent knowledge of the physiological mechanism underlying the disease time course. Adopting a system-theoretic paradigm, a population response model is developed where the clinical endpoint is described as a function of the patient's health state. In particular, a continuous-time stochastic approach is proposed where the clinical score and its time-derivative summarize the patient's health state affected by a random term accounting for exogenous unpredictable factors. The proposed approach is validated on experimental data from the placebo and drug arms of a Phase II depression trial. Since some subjects in the trial may undergo changes in their treatment dose due to the flexible dosing scheme, dose escalations are modelled as instantaneous perturbations on the state. In its simplest form--an integrated Wiener process--was able to correctly capture the individual responses in both treatment arms. However, a better description of inter-individual variability was obtained by means of a stable Markovian model. Parameter estimation has been carried out according to the empirical Bayes method.

A convolution-based in vitro-in vivo correlation model for methylphenidate hydrochloride delayed-release and extended-release capsule.

Delayed-release and extended-release methylphenidate hydrochloride (JORNAY PM®) is a novel capsule formulation of methylphenidate hydrochloride, used to treat attention deficit hyperactivity disorder in patients 6 years and older. In this paper, we develop a Level A in vitro-in vivo correlation (IVIVC) model for extended-release methylphenidate hydrochloride to support post-approval manufacturing changes by evaluating a point-to-point correlation between the fraction of drug dissolved in vitro and the fraction of drug absorbed in vivo. Dissolution data from an in vitro study of three different release formulations: fast, medium, and slow, and pharmacokinetic data from two in vivo studies were used to develop an IVIVC model using a convolution-based approach. The time-course of the drug concentration resulting from an arbitrary dose was considered as a function of the in vivo drug absorption and the disposition and elimination processes defined by the unit impulse response function using the convolution integral. An IVIVC was incorporated in the model due to the temporal difference seen in the scatterplots of the estimated fraction of drug absorbed in vivo and the fraction of drug dissolved in vitro and Levy plots. Finally, the IVIVC model was subjected to evaluation of internal predictability. This IVIVC model can be used to predict in vivo profiles for different in vitro profiles of extended-release methylphenidate hydrochloride.

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.

Monoamine transporter occupancy of a novel triple reuptake inhibitor in baboons and humans using positron emission tomography.

The selection of a therapeutically meaningful dose of a novel pharmaceutical is a crucial step in drug development. Positron emission tomography (PET) allows the in vivo estimation of the relationship between the plasma concentration of a drug and its target occupancy, optimizing dose selection and reducing the time and cost of early development. Triple reuptake inhibitors (TRIs), also referred to as serotonin-norepinephrine-dopamine reuptake inhibitors, enhance monoaminergic neurotransmission by blocking the action of the monoamine transporters, raising extracellular concentrations of those neurotransmitters. GSK1360707 [(1R,6S)-1-(3,4-dichlorophenyl)-6-(methoxymethyl)-4-azabicyclo[4.1.0]heptane] is a novel TRI that until recently was under development for the treatment of major depressive disorder; its development was put on hold for strategic reasons. We present the results of an in vivo assessment of the relationship between plasma exposure and transporter blockade (occupancy). Studies were performed in baboons (Papio anubis) to determine the relationship between plasma concentration and occupancy of brain serotonin reuptake transporter (SERT), dopamine reuptake transporter (DAT), and norepinephrine uptake transporter (NET) using the radioligands [(11)C]DASB [(N,N-dimethyl-2-(2-amino-4-cyanophenylthio) benzylamine], [(11)C]PE2I [N-(3-iodoprop-2E-enyl)-2ß-carbomethoxy-3ß-(4-methylphenyl)nortropane], and [(11)C]2-[(2-methoxyphenoxy)phenylmethyl]morpholine (also known as [(11)C]MRB) and in humans using [(11)C]DASB and [(11)C]PE2I. In P. anubis, plasma concentrations resulting in half-maximal occupancy at SERT, DAT, and NET were 15.16, 15.56, and 0.97 ng/ml, respectively. In humans, the corresponding values for SERT and DAT were 6.80 and 18.00 ng/ml. GSK1360707 dose-dependently blocked the signal of SERT-, DAT-, and NET-selective PET ligands, confirming its penetration across the blood-brain barrier and blockade of all three monoamine transporters in vivo.

Exposure-response modeling of anti-depressant treatments: the confounding role of placebo effect.

Emerging evidence indicates that the selection of patients and the selection of recruitment centers in placebo-controlled, randomized clinical trials (RCTs) in depression have a substantial impact on the probability of observing a treatment effect of a novel medication. The objective of this work was to evaluate the role of placebo in characterizing the exposure-response relationship and proposes a new methodology based on band-pass filtering for assessing the relationship between drug exposure, level of clinical response conditioned to the level of placebo response, and the potency of the antidepressant drug evaluated. Clinical trial simulation (CTS) was used to demonstrate that the conventional analyses of data generated in multi-centre RCTs including centres exhibiting heterogeneous placebo response can lead to contradictory and inappropriate assessment of the exposure-response relationship. To address this issue, a novel modelling approach has been developed for establishing the exposure-response relationship by using a pharmacodynamic model accounting for the placebo effect. The proposed model demonstrated that the expected drug related treatment effect in a placebo-controlled RCT can be predicted as a function of the dose, the drug potency and the level of placebo response when data from informative recruitment centres are considered. With this novel approach, a more accurate estimate of the dose/exposure response can be derived and more informed go/no-go decisions can be made in developing drugs for psychiatric disorders.

A PCA approach to population analysis: with application to a Phase II depression trial.

For psychiatric diseases, established mechanistic models are lacking and alternative empirical mathematical structures are usually explored by a trial-and-error procedure. To address this problem, one of the most promising approaches is an automated model-free technique that extracts the model structure directly from the statistical properties of the data. In this paper, a linear-in-parameter modelling approach is developed based on principal component analysis (PCA). The model complexity, i.e. the number of components entering the PCA-based model, is selected by either cross-validation or Mallows' Cp criterion. This new approach has been validated on both simulated and clinical data taken from a Phase II depression trial. Simulated datasets are generated through three parametric models: Weibull, Inverse Bateman and Weibull-and-Linear. In particular, concerning simulated datasets, it is found that the PCA approach compares very favourably with some of the popular parametric models used for analyzing data collected during psychiatric trials. Furthermore, the proposed method performs well on the experimental data. This approach can be useful whenever a mechanistic modelling procedure cannot be pursued. Moreover, it could support subsequent semi-mechanistic model building.

Artificial intelligence approach for the analysis of placebo-controlled clinical trials in major depressive disorders accounting for individual propensity to respond to placebo.

Treatment effect in clinical trials for major depressive disorders (RCT) can be viewed as the resultant of treatment specific and non-specific effects. Baseline individual propensity to respond non-specifically to any treatment or intervention can be considered as a major non-specific confounding effect. The greater is the baseline propensity, the lower will be the chance to detect any treatment-specific effect. The statistical methodologies currently applied for analyzing RCTs doesn't account for potential unbalance in the allocation of subjects to treatment arms due to heterogenous distributions of propensity. Hence, the groups to be compared may be imbalanced, and thus incomparable. Propensity weighting methodology was used to reduce baseline imbalances between arms. A randomized, double-blind, placebo controlled, three arms, parallel group, 8-week, fixed-dose study to evaluate efficacy of paroxetine CR 12.5 and 25 mg/day is presented as a cases study. An artificial intelligence model was developed to predict placebo response at week 8 in subjects assigned to placebo arm using changes from screening to baseline of individual Hamilton Depression Rating Scale items. This model was used to predict the probability to respond to placebo in each subject. The inverse of the probability was used as weight in the mixed-effects model applied to assess treatment effect. The analysis with and without propensity weight indicated that the weighted analysis provided an estimate of treatment effect and effect-size about twice larger than the non-weighted analysis. Propensity weighting provides an unbiased strategy to account for heterogeneous and uncontrolled placebo effect making patients' data comparable across treatment arms.

A new method for analyzing clinical trials in depression based on individual propensity to respond to placebo estimated using artificial intelligence.

One of the major reasons for trial failures in major depressive disorders (MDD) is the presence of unpredictable levels of placebo response as the individual baseline propensity to respond to placebo is not adequately controlled by the current randomization and statistical methodologies. The individual propensity to respond to any treatment or intervention assessed at baseline was considered as a major non-specific prognostic and confounding effect. The objective of this paper was to apply the propensity score methodology to control for potential imbalance at baseline in the propensity to respond to placebo in clinical trials in MDD. Individual propensity was estimated using artificial intelligence (AI) applied to observations collected in two pre-randomization occasions. Cases study are presented using data from two randomized, placebo-controlled trials to evaluate the efficacy of paroxetine in MDD. AI models were used to estimate the individual propensity probability to show a treatment non-specific placebo effect. The inverse of the estimated probability was used as weight in the mixed-effects analysis to assess treatment effect. The comparison of the results obtained with and without propensity weight indicated that the weighted analysis provided an estimate of treatment effect and effect size significantly larger than the conventional analysis.

Interpreting clinical trial outcomes complicated by placebo response with an assessment of false-negative and true-negative clinical trials in depression using propensity-weighting.

The objective of this study was to evaluate the performances of the propensity score weighted (PSW) methodology in a post-hoc re-analysis of a failed and a negative RCTs in depressive disorders. The conventional study designs, randomizations, and statistical approaches do not account for the baseline distribution of major non-specific prognostic and confounding factors such as the individual propensity to show a placebo effect (PE). Therefore, the conventional analysis approaches implicitly assume that the baseline PE is the same for all subjects in the trial even if this assumption is not supported by our knowledge on the impact of PE on the estimated treatment effect (TE). The consequence of this assumption is an inflation of false negative results (type II error) in presence of a high proportion of subjects with high PE and an inflation of false positive (type I error) in presence of a high proportion of subjects with low PE value. Differently from conventional approaches, the inverse of the PE probability was used as weight in the mixed-effects analysis to assess TE in the PSW analysis. The results of this analysis indicated an enhanced signal of drug response in a failed trial and confirmed the absence of drug effect in a negative trial. This approach can be considered as a reference prospective or post-hoc analysis approach that minimize the risk of inflating either type I or type II error in contrast to what happens in the analyses of RCT studies conducted with the conventional statistical methodology.

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.

Efficacy of Amphetamine Extended-Release Oral Suspension in Children with Attention-Deficit/Hyperactivity Disorder: Effect Size Across the Day.

Objective: To evaluate the treatment effect size throughout the day of amphetamine extended-release oral suspension (AMPH EROS; Tris Pharma, Inc., Monmouth Junction, NJ, USA) in a laboratory classroom study conducted in children aged 6-12 years with attention-deficit/hyperactivity disorder (ADHD). Methods: A post hoc analysis was performed to assess the overall effect size as well as the effect size at each time point from early morning through evening (1, 2, 4, 6, 8, 10, 12, and 13 hours postdose) for each efficacy measure evaluated in a 5-week, randomized, dose-optimized, double-blind, placebo-controlled, laboratory classroom assessment, efficacy, and safety study of AMPH EROS (N = 99). Change from baseline of the primary (Swanson, Kotkin, Agler, M-Flynn, Pelham [SKAMP]-C) and key secondary (secondary efficacy assessments included the SKAMP attention [SKAMP-A], SKAMP-deportment subscale [SKAMP-D], Permanent Product Measure of Performance-number of problems attempted [PERMP-A], PERMP-number of problems correct [PERMP-C]) efficacy measures were analyzed using a linear mixed model repeated-measures analysis model. Comparisons among treatments were adjusted for multiple comparisons using the Bonferroni method. The effect size was estimated using Cohen's d, to determine "small," (0.2), "medium," (0.5), or "large" (0.8) magnitudes of treatment effects. Results: Large overall effect sizes were observed for all primary and key secondary efficacy assessments. Moreover, the SKAMP-C, PERMP-number of problems attempted, and PERMP-C scores showed large effect sizes at each time point evaluated across the day, from 1 to 13 hours postdose. The SKAMP-A and SKAMP-D scores showed a medium to large effect size at each time point. Conclusions: AMPH EROS demonstrated a large and consistent effect size across the day, including early in the morning, in the treatment of symptoms of ADHD in children aged 6-12 years. Trial Registration: clinicaltrials.gov identifier: NCT02083783.

A pharmacokinetic PET study of NK1 receptor occupancy.

PURPOSE: There is growing recognition of the importance of integrating drug occupancy data acquired by positron emission tomography (PET) with the plasma pharmacokinetics of the drug, in order to establish proper dose selection in subsequent clinical trials. Here we present a study in human subjects of the occupancy of NK(1) receptors achieved following different doses of casopitant, a selective NK(1) antagonist. METHODS: Two PET scans were carried out in each of eight human subjects, with the PET radioligand [(11)C]GR205171, a high-affinity and selective NK(1) receptor antagonist. The first scan was under baseline conditions and the second 24 h after a single oral dose of casopitant (2-120 mg). Arterial blood was collected throughout the scans for determination of plasma and whole blood input functions. Venous blood samples were taken prior to and following oral dosing up to 24 h for a pharmacokinetic study of casopitant concentration in plasma. RESULTS: It was first necessary to establish a suitable kinetic model for the estimation of [(11)C]GR205171 NK(1) receptor binding parameters in human brain tissue. A three-tissue compartment model with simultaneous estimation of multiple regions sharing common variables across regions was found suitable for the analysis. Because of the injected cold mass of the tracer and the high affinity of [(11)C]GR205171 a correction for tracer occupancy effects was also incorporated into the analysis. We then developed a pharmacokinetic-receptor occupancy (PK-RO) model of the relationship between casopitant plasma concentrations and receptor binding, using a population approach. CONCLUSION: These results indicate that after chronic dosing, casopitant can achieve a degree of NK(1) receptor occupancy higher than those that have previously been tested in studies of clinical depression.