Pharmacokinetic and Pharmacodynamic Properties of Lisdexamfetamine in Adults with ADHD

1. Pharmacokinetic and Pharmacodynamic Properties of Lisdexamfetamine in Adults with ADHD Len Adler, Samuel Alperin, Stephen V. Faraone, NYU School of Medicine, Hofstra North-Shore/LIJ Medical School, SUNY Upstate Medical University BACKGROUND: Lisdexamfetamine (LDX) is a pro-drug (d-amphetamine (d-amph) bound to lysine). Clinically, d-amph is available post-cleavage of the pro-drug in the blood stream. Clinical effects of LDX in ADHD have been shown to persist up to 14 hours; however pharmacokinetic (PK) data of LDX and Amph in ADHD adults is not currently available. OBJECTIVES: 1) to examine PK data of plasma Amph and LDX levels and 2) to compare PK data with Time Sensitive ADHD Rating Scale (TASS) ratings (PK v. PD). METHODS: Plasma Amph/LDX levels and TASS ratings were obtained immediately prior to AM dose and then 0.5, 1, 2, 4, 6, 8, 10 and 12 hours post-dosing in 21 adults with ADHD treated with five weeks of single-blind LDX up to 70 mg/day (after 1 week single-blind PBO). RESULTS: LDX levels peaked at 1.5 hours after administration (T max ) and then rapidly declined (levels were negligible at 6 hours), (area under the curve (AUC) = 45.9, Cmax = 25.0, and half-life (t1⁄2) = 0.5 hours). Amph levels peaked at (T max) 4.4 hours, but then slowly declined (AUC = 641.6, Cmax = 67.9, and t 1⁄2 = 17.0 hours). No significant correlations were seen between d-amph levels and TASS scores. CONCLUSIONS: 1) pro-drug LDX levels peaked fairly rapidly and declined, while Amph levels peaked 3 hours later than LDX levels and persisted throughout the day and 2) the absence of PK/PD correlations may be due to subjects remaining in a controlled, non-attention demanding environment, potentially distorting TASS ratings. 3. Examination of Transgenerational Transmission of ADHD through the WHO ASRS v1.1 Screener Samuel Alperin, Len Adler Hofstra North-Shore/LIJ Medical School, NYU School of Medicine, OBJECTIVES: To examine: 1) transgenerational transmission of ADHD via the ASRS v1.1 Screener in parents of children with ADHD, 2) potential contributions of socioeconomic status (SES)and executive function (EF) to the screen positive cohort. METHODS: Parents of children diagnosed with ADHD at the NYU School of Child Study Center (CSC) were identified via record search of the electronic database. Subjects who agreed to participate received a survey via the telephone which included: 1) the 6-question ASRS Screener v1.1, 2) a supplemental 6 questions exploring EF, and 3) demographical questions including the Hollingshead SES Questionnaire. RESULTS: The screen positive rate of parents of children with ADHD was 19.1%. There were no statistically significant differences in age, gender, race or SES between the screen positive and screen negative groups. The ASRS v.1.1 screen positive group had significantly higher average total EF score and a significantly greater number of EF symptoms at “significant level” (>= 3 “often”). A post-hoc factor analysis revealed three factors: Inattention (IA), HyperactivityImpulsivity (HI) and EF. CONCLUSIONS: 1) The screen positive rate on the ASRS v1.1 Screener was higher than that found in the general population, but somewhat less than the expected rate, given reported prevalence rates of 30%-40% in parents of children with ADHD. 2) A factor analysis revealed three factors of IA, HI and EF, similar to the findings of a large community based survey of ADHD symptoms (Kessler RC et al. 2010). 3) The screen positive cohort scored higher on questions of executive function. 4. Hypoconnectivity in Default Network Subsystems on Resting fMRI is Correlated with ADHD Hyperactive-Impulsive Symptoms Lisa Alder, Xavier Castellanos George Washington University School of Medicine, New York University School of Medicine The default network, which is implicated in the representation of thoughts and cognition about oneself, is defined by increased BOLD activity during rest compared to when performing a task. A subcomponent of the default network, the dorsal medial prefrontal cortex (dMPFC) has been related to thinking about oneself in the present, while another subcomponent, the medial temporal lobe system (MTL) has been related to thinking about oneself in the future. Based on observations that individuals with ADHD tent to ignore the future consequences of their actions, leading to poor decision-making, we examined differences in intrinsic functional connectivity between these two default network systems in relation to a variety of ADHD symptom domains, as assessed by clinical rating scales, in a sample of 61 adults with ADHD and 75 controls. Significant positive correlations were found between the differences in default network BOLD activations between these two subsystems and subjects’ standardized scores on subscales measuring hyperactivity, impulsivity and ADHD Total Symptoms of the Conners’ Adult ADHD Rating Scale (CAARS), but only among those subjects who had T-score ≥ 65 on the CAARS DSM-IV Inattentive Symptoms Subscale. These results provide evidence of a dimensional relationship between severity of hyperactive and impulsive symptoms among these adults, with the degree of default network hypoconnectivity between its “now” and “future” subsystems. This suggests a potential brain-behavior relationship between dMPFC and MTL subsystem hypoconnectivity among more hyperactive and impulsive individuals which could underlie poor decision making observed among many individuals with ADHD. 5. Neural Mechanisms Underlying the Therapeutic Actions of Guanfacine Treatment in Youth with ADHD: A Pilot fMRI Study Anne Claude-Bedard, Kurt Schulz, Beth Krone, Juan Pedraza, Stephanie Duhoux, Jeffrey Halperin, Jeffrey Newcorn Icahn School of Medicine at Mount Sinai, Queens College of the City University of New York Twenty-five youth with attention-deficit/hyperactivity disorder (ADHD) were scanned with functional magnetic resonance imaging while performing a go/no-go task before and after six to eight weeks of randomized once-daily treatment with either the α2A adrenergic receptor agonist guanfacine or placebo. Clinical improvement was greater for guanfacine than placebo and was differentially associated with reduced activation for guanfacine compared to placebo in right midcingulate cortex/supplementary motor area and left posterior cingulate cortex. Findings point to both common and unique mechanisms of action in relation to other stimulant and nonstimulant medications for ADHD. 6. Metadoxine Affects Brain Activity in Neural Circuits Associated with Cognitive Dysfunctions: A Pharmacological MRI Study in Conscious Rats Johanna Schumann, Jonathan Rubin, Craig Ferris, Mark Nedelman, Yaron Daniely Alcobra Ltd, Center for Translational NeuroImaging, Northeastern University, Ekam Imaging Metadoxine Extended Release (MDX) previously showed cognitive improvement in clinical trials in adults with ADHD. To further elucidate brain activity of metadoxine, brain responses to metadoxine and its components, Pyridoxine and L-Pyroglutamic acid (L-PGA), were investigated using pharmacological magnetic resonance imaging (phMRI), based on blood oxygen level-dependent (BOLD) contrast. When fully conscious, rats were administered a single intraperitoneal injection of vehicle, 75 or 150 mg/kg metadoxine, pyridoxine or L-PGA (75 mg/kg) and subjected to phMRI. Images were acquired every 6 seconds for 60-minutes and registered to a 3D rat brain atlas for analysis. Metadoxine exhibited widespread negative BOLD activity in 28 brain regions and significant increased positive BOLD in only 7 of the 170 regions evaluated. The main areas displaying significant increased negative BOLD include the prefrontal cortex (PFC) (including prelimbic, 2 motor, medial orbital, anterior cingulate), thalamus, caudate putamen, subregions of the cerebellum and primary somatosensory areas, regions associated with executive function, motivation, information processing and cognition. None of the mesolimbic dopamine system areas involved in reinforcing effects of scheduled drugs were affected by metadoxine. Metadoxine displayed a distinct phMRI fingerprint compared with approved ADHD therapies, the main difference being fewer areas exhibiting positive BOLD and a lack of effect on abuserelated areas. Metadoxine fingerprint was additionally distinct from its components. Metadoxine’s potential inhibitory effect on neuronal hyperactivity in cortical, striatal and verebellar regions could explain its precognitive activity. These findings extend previous data demonstrating a novel monamine-independent mechanism of action of metadoxine characterized by GABAergic inhibitory transmission modulation. Two sentence summary: Pharmacologic magnetic resonance imaging of conscious rat using brain oxygen level dependent contrast demonstrated a fingerprint of reduced neuronal activity by metadoxine distinct from other ADHD medications. This fingerprint was characterized by reduced activity in areas thought to be hyperactivated in ADHD, as well as an absence of activity in areas of the brain associated with abuse. 7. Metadoxine A Novel Synaptic Transmission Modulator with Low Abuse Potential in Development for Attention Deficit Hyperactivity Disorder (ADHD) Johanna Schumann, Jonathan Rubin, Yaron Daniely, Sharon L. Smith, Helen L. Rowley, David J. Heal, Amyaouch Bradaia, Bruno Buisson Alcobra Ltd, RenaSci Ltd, Neuroservice OBJECTIVE: Metadoxine Extended Release (MDX) has shown positiove results in clinical trials in adults with ADHD. To elucidate its mechanism of action, we have investigated (a) the neurochemical effect of metadoxine by microdialysis in rats (b) the electrophysiological effect on striatal medium spiny neurons and (c) its potential reinforcing effect in a self-administration model. METHODS: Norepinephrine (NP), dopamine (DA) and serotonin (5 HT) levels were measured by microdialysis in rat prefrontal cortex (PFT) and striatum (STR) after a single oral dose of metadoxine (150 or 300 mg/kg). Passive membrane properties and miniature inhibitory postsynaptic currents (miPSC) were recorded from mice cortostritial slices treated with metadoxine (100, 200 or 300 μM) using whole-cell patch clamp. Self-administration was conducted in rates, first trained with methylphenidate (0.1 mg/kg, iv) on a fixed ration 2 schedule of reinforcement and then tested with metadoxine (0.3, 1.0, 3.0 or 10 mg/kg, iv). RESULTS: Microdialysis did not reveal any effect of methadoxine on extracellular levels of DA, NE or 5-HT in PFC or STR. While metadoxine did not cause any effect on cell membrance properties, it showed a dose-dependent increase of mlPSCs frequency, indicating enhanced gamma-aminobutyric acid (GABA)ergic synaptic transmission via a presynaptic effect. Metadoxine did not serve as a positive reinforce. CONCLUSIONS: The results demonstrate that metadoxine displays a novel monamineindependent mechanism of action that may be associated with synaptic transmission and cognitive regulation and may lack abuse potential in humans. Two sentence summary: Metadoxine did not show any effect on levels of monamines measured by microdialysis, and it did not serve as a positive reinforce. These findings, combined with a novel MOA characterized by facilitation of GABAergic inhibitory transmission, provide evidence for reduced abuse potential and pro-cognitive properties. 8. Clinical Correlates of Working Memory Deficits: A Controlled Study of Children with and without ADHD Joseph Biederman, Ronna Fried, James Chan, Leah Feinberg, Brittany Hughes Massachusetts General Hospital; Harvard Medical School, Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Massachusetts General Hospital; Department of Psychiatry, Harvard Medical School, Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Massachusetts General Hospital; Department of Psychiatry, Harvard Medical School, Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Massachusetts General Hospital BACKGROUND: Major sources of morbidity and disability in ADHD are deficits in executive functions, of which the ability to hold information in memory for short time periods (working memory, FKA freedom from distractibility) is a prominent component. The main aim of this analysis was to clarify the implications of such deficits among youth with ADHD. METHODS: Subjects were youth with (N=259) and without (N=222) ADHD ascertained from pediatric and psychiatric clinics. Assessments included measures of psychiatric, psychosocial, educational, and cognitive functioning. Subjects were split into four groups: subjects with ADHD and FFDD (ADHD+FFDD), subjects with ADHD and no FFDD (ADHD), subject with FFDD and no ADHD (FFDD + Controls), and subjects with no FFDD and no ADHD (Controls). RESULTS: Significantly more youth with ADHD had freedom from distractibility deficits (FFDD) than controls. ADHD with FFDD was associated with an increased risk for grade retention and a decrease in academic achievement relative to ADHD alone, controlling for SES, learning disabilities, and IQ. No differences were noted in social functioning or psychiatric comorbidity. CONCLUSIONS: Youth with ADHD and FFDD are at high risk for significant impairments in academic functioning. These results support screening children with ADHD for Working Memory deficits so that interventions can be implemented to prevent academic failure. 9. Further Evidence that Severe Scores in the Aggression/Anxiety-Depression/Attention Subscales of Child Behavior Checklist (Severe Dysregulation Profile) Can Screen for Bipolar Disorder Symptomatology: A Conditional Probability Analysis Joseph Biederman, Mai Uchida, Stephen V. Faraone, Tara Kenworthy, K. Yvonne Woodworth, Jacqueline Davis, Thomas Spencer, Janet Wozniak Massachusetts General Hospital; Harvard Medical School, Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Massachusetts General Hospital; Department of Psychiatry, Harvard Medical School, Departments of Psychiatry and of Neuroscience and Physiology, SUNY Upstate Medical University, Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Massachusetts General Hospital, Clinical and Research Programs in Pediatric Psychopharmacology and Adult ADHD, Massachusetts General Hospital; Department of Psychiatry, Harvard Medical School BACKGROUND: Previous work shows that children with high scores (2 SD, combined score ≥ 210) on the Attention Problems, Aggressive Behavior, and Anxious-Depressed (A-A-A) subscales of the Child Behavior Checklist (CBCL) are more likely than other children to meet criteria for bipolar (BP)-I disorder. However, the utility of this profile as a screening tool has remained unclear. METHODS: We compared 140 patients with pediatric BP-I disorder, 83 with attention deficit hyperactivity disorder (ADHD), and 114 control subjects. We defined the CBCL-Severe Dysregulation profile as an aggregate cutoff score of ≥ 210 on the A-A-A scales. Patients were assessed with structured diagnostic interviews and functional measures. RESULTS: Patients with BP-I disorder were significantly more likely than both control subjects (Odds Ratio [OR]: 173.2; 95% Confidence Interval [CI], 21.2 to 1413.8; P < 0.001) and those with ADHD (OR: 14.6; 95% CI, 6.2 to 34.3; P < 0.001) to have a positive CBCL-Severe Dysregulation profile. Receiver Operating Characteristics analyses showed that the area under the curve for this profile comparing children with BP-I disorder against control subjects and those with ADHD was 99% and 85%, respectively. The corresponding positive predictive values for this profile we 99% and 92% with false positive rates of < 0.2% and 8% for the comparisons with control subjects and patients with ADHD, respectively. LIMITATIONS: Non-clinician raters administered structured diagnostic interviews, and the sample was referred and largely Caucasian. CONCLUSIONS: The CBCL-Severe Dysregulation profile can be useful as a screen for BP-I disorder in children in clinical practice. 10. Assessing Validity of "age of onset" Criteria for Diagnosis of ADHD in DSM-5 Shanel Chandra, Stephen Faraone, Joseph Biederman SUNY Upstate Medical University, Massachusetts General Hospital; Harvard Medical School OBJECTIVE: Convincing data about the age of onset criterion for diagnosing ADHD in DSMIV led to the increase in age of onset to twelve in DSM-V. The present work attempted to clarify the validity of ADHD when diagnosticians cannot establish an onset prior to the DSM-V criterion of age twelve. METHOD: We addressed the validity of DSM-V’s age at onset criteria by comparing three groups of adults: a) Full ADHD subjects met all DSM-V criteria for childhood onset ADHD (N=182); b) Late-Onset ADHD subjects met all criteria except the age at onset criterion (N=17), and c) non-ADHD subjects did not meet any of the above criteria (N=117). We hypothesized that Late Onset ADHD would show patterns of symptoms, psychiatric comorbidity, functional impairment, familial transmission, quality of life measures, social adjustment and intelligence levels similar to that seen for Full ADHD subjects. RESULTS: Full ADHD had more inattentive symptoms, scored more on sense of well-being, overall life satisfaction and functioning in daily life measures in quality of life assessment scale, and had a lower social adjustment scores compared to Late-onset ADHD subjects. Both groups had similar patterns of psychiatric comorbidity, functional impairment, familial transmission and intelligence. CONCLUSIONS: Our data suggests comparable clinical features and co-morbidities in FullADHD and Late onset ADHD groups when applying DSM-V’s age of onset criteria. Our results suggest that Late-Onset adult ADHD is still valid even after discarding the DSM-V age of onset criterion. 11. Resting Functional Connectivity in Children with Attention Deficit/Hyperactivity Disorder (ADHD) Lucas Battel, Renata Keiling, Lucas Canzi Ames, Luis Augusto Rohde, Christian Kieling, Nathassia Aurich and Alexandre Franco 1Universidade Federal do Rio Grande do Sul, Hospital de Clínicas de Porto Alegre Attention deficit/hyperactivity disorder (ADHD) is one of the most prevalent neuropsychiatric disorders among children. Although the clinical presentation and treatment of ADHD are well established, its etiology is not yet known. Recent functional neuroimaging techniques may help increase knowledge about the pathophysiology of the disorder, allowing for the empirical testing of theoretical hypotheses on brain networks in ADHD. In this study, we analyzed a group of 23 treatment naïve boys with ADHD, aged between 8 and 10 years old, who underwent a protocol of resting-state functional magnetic imaging before and after six months of treatment with methylphenidate. Functional connectivity in the default mode network (DMN) was assessed before and after treatment using regions of interest (ROI) and independent component analysis (ICA). Results of the seeds analysis showed no significant changes in connectivity between regions of the DMN following treatment, with a relatively small increase in the anterior-posterior connectivity of the network. The ICA revealed a significant increase in the connectivity between the left putamen and the DMN (p <0.01, corrected). There was also a positive correlation between the decrease of symptoms and the connectivity between the putamen and the DMN after treatment (rho=-0.65, p=0.017). These findings suggest that treatment with methylphenidate might modify the connectivity between the DMN and subcortical nuclei. Dysfunctions in cortical-subcortical circuits have often been associated with the pathophysiology of ADHD. The effect of treatment with methylphenidate may in part be associated with elevated dopamine levels in subcortical nuclei, modulating its connectivity with the DMN. 12. The Single Dose Pharmacokinetics of HLD200: A Modified Release Methylphenidate (MPH) Formulation in Children and Adolescents with Attention-Deficit/Hyperactivity Disorder (ADHD) Ann Childress, Bev Incledon, Albert Agro, Angus McLean Center for Psychiatry and Behavorial Medicine, Inc., Ironshore Pharmaceuticals & Development, Inc. OBJECTIVE: The objective of this study was to examine safety and tolerability and to evaluate the single dose pharmacokinetics of orally administered HLD200 in the evening to children and adolescents with ADHD. The study design allowed pharmacokinetic parameters in children and adolescents to be compared. BACKGROUND: Although several effective extended-release methylphenidate (MPH) products are available, early morning ADHD symptoms remain problematic for patients and their caregivers. HLD200 is a novel delayed and extended-release oral capsule formulation of MPH. When administered in the evening before bedtime, HLD200 is formulated to delay the initial release of MPH approximately 8-hours, coincident with the early morning pre-awakening period, in order to provide an onset of clinically significant treatment effect immediately upon awakening and throughout the patient’s early morning routine. Additionally, HLD200’s novel extended-release drug profile is designed to provide significant treatment effect throughout the remaining periods of the day currently targeted by conventional extended-release formulations. METHOD: This trial was a Phase I/II, single site, open-label PK study in children and adolescents diagnosed with ADHD. A total of 29 male and female subjects (11 aged 6 to 12 years old; and 18 aged 13 to 17 years) who had previously been treated with MPH received a single oral dose of 54 mg HLD200 (equivalent to approximately 40 mg MPH in vivo). The study was IRB-approved and all subjects/parents provided assent/consent to participate in the trial. Screening included administration of the MINI International Neuropsychiatric Interview for Children and Adolescents (MINI-KID) to confirm ADHD Diagnosis, physical exam, ECGs, collection of laboratory data and urine drug screen. Subjects were required to discontinue ADHD treatments for at least five days prior to dosing with HLD200. Eligible subjects were admitted to the study facility at approximately 3 PM prior to dosing and remained there until approximately 9 PM the next day. After an updated medical history, drug screen, ECGs and physical exam, eligibility was confirmed. A catheter was then inserted and pre-dose labs and PK samples were collected. HLD200 (54 mg) dosing occurred at approximately 9 PM. Subjects consumed a low fat meal approximately four hours prior to dosing. After an overnight fast, subjects were encouraged to eat meals and snacks and to stay well hydrated in order to improve tolerability to PK sampling. PK samples (4mL) were collected prior to dosing (t=0) and following dosing at t=4, 6, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 24, 36 and 48 hours to determine plasma MPH concentration. Vital signs were collected prior to each PK draw and multiple electrocardiograms were collected during the trial. Plasma samples were analyzed by MPH in plasma using high performance liquid chromatography with Tandem Mass spectrometry (LC-MS/MS). Overall, the inter-assay precision (%CV) and accuracy (%Bias) ranged from 1.6% to 2.7% and from –2.9% to 3.4%, respectively. RESULTS: Plasma MPH parameters are shown in the Table 1 below. Mean values of body weight-adjusted maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax) and area under the concentration-time curve (AUC) were similar among children and adolescents. The concentration-time profile of HLD200 is depicted graphically in Figure 1 and Figure 2 (dose-body weight corrected). As would be expected, variability in drug exposure between children and adolescents appears to be due to weight differences; as weight corrected values are very similar between the two groups. There were no serious adverse events (AEs) and the most common treatment emergent adverse events (TEAEs), thought to be possibly or probably drug-related, were those predictably reported with MPH. These AEs were mild and included upper abdominal pain (2 occurrences), intermittent headaches, emesis and flatulence (one occurrence each). Although the subjects were awakened to obtain PK samples, there were no reported spontaneous difficulties with appetite, sleep latency, middle of the night awakenings, or early morning awakenings. Table 1: Mean (SD) Plasma Methylphenidate Pharmacokinetic Parameters in Children and Adolescents with ADHD following a Single Oral 54 mg dose of HLD200 PK Parameter 6-12 years 13-17 years