ObjectiveExtended-release methylphenidate (ER-MPH) formulations used to treat attention deficit hyperactivity disorder (ADHD) have complex pharmacokinetic (PK) profiles, resulting from differing ...ratios of immediate-release and extended-release components and/or their site of absorption. This study aimed to evaluate the smoothness of PK curves of ER-MPHs. DesignThe integral of the second derivative squared was evaluated for modeled PK curves, with smaller values indicating a smoother curve. The calculated smoothness of each PK curve was normalized by dividing by Cmax 2 to derive a normalized smoothness parameter appropriate across the dose range of each formulation. Calculations used modeled PK curves from 100mg delayed-release and ER-MPH (DR/ER-MPH), 54mg osmotic release oral system MPH (OROS MPH), 60mg MPH controlled-release delivery (MPH CD), 60mg ER-MPH oral suspension (MEROS), 20mg ER dexmethylphenidate (d-MPH ER), and 60mg multilayer-release MPH (MLR-MPH). ResultsThe Cmax2-normalized smoothness value was consistent across DR/ER-MPH doses, allowing for relevant comparisons across formulations. Normalized smoothness values differed widely; the lowest normalized smoothness was 0.05 with DR/ER-MPH and ranged up to 9.56 with d-MPH ER. ConclusionDR/ER-MPH demonstrated a smoother PK profile compared to the highest dose of other ER-MPH formulations. While the benefits of a smooth PK profile remain to be tested clinically, having fewer peaks and troughs has been hypothesized to reduce waxing and waning of therapeutic effects throughout the day, and more gradual changes in MPH plasma levels have been hypothesized to lower the risk of likeability and potentially abate afternoon symptom rebound.
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 E
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.
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.
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.
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.
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.
One of the main reasons for the inefficiency of multicenter randomized clinical trials (RCTs) in depression is the excessively high level of placebo response. The aim of this work was to propose a ...novel methodology to analyze RCTs based on the assumption that centers with high placebo response are less informative than the other centers for estimating the 'true' treatment effect (TE). A linear mixed-effect modeling approach for repeated measures (MMRM) was used as a reference approach. The new method for estimating TE was based on a nonlinear longitudinal modeling of clinical scores (NLMMRM). NLMMRM estimates TE by associating a weighting factor to the data collected in each center. The weight was defined by the posterior probability of detecting a clinically relevant difference between active treatment and placebo at that center. Data from five RCTs in depression were used to compare the performance of MMRM with NLMMRM. The results of the analyses showed an average improvement of ~15% in the TE estimated with NLMMRM when the center effect was included in the analyses. Opposite results were observed with MMRM: TE estimate was reduced by ~4% when the center effect was considered as covariate in the analysis. The novel NLMMRM approach provides a tool for controlling the confounding effect of high placebo response, to increase signal detection and to provide a more reliable estimate of the 'true' TE by controlling false negative results associated with excessively high placebo response.
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).
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.
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.
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.
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