This open-label, single-dose, randomized, two-period, two-treatment, two-sequence, crossover study evaluated the comparative bioavailability between amphetamine extended-release oral suspension ...(treatment A: AMPH EROS, Dyanavel XR 2.5 mg/mL, 18.8 mg amphetamine base per 7.5 mL) and extended-release mixed amphetamine salts (treatment B: ER MAS, Adderall XR 30 mg capsules, equivalent to 18.8 mg amphetamine base per capsule) after a single dose in healthy adult subjects, under fasted conditions.
The crossover design allowed for intra-subject PK comparisons. Relative comparable bioavailability was determined by a statistical comparison of the AUC and Cmax parameters for both d- and l-amphetamine, where the geometric mean ratios for AUC and Cmax were within the 90% confidence limits (80.0%-125.0%) to determine comparable bioavailability between test products. Subjects in sequence 1 received treatment A followed by B; subjects in sequence 2 received treatment B followed by treatment A. PK samples were obtained at 0 (pre-dose) through 60 hours post-dose. The safety assessment was based on reported frequency and severity of adverse events.
Thirty (30) subjects were enrolled and 28 completed. The mean age of subjects was 35 years, with a mean BMI of 25.9 kg/m2. Most subjects were Male (63.3%) and Black (56.7%). The geometric mean ratios for Cmax and all AUC measurements were within the 80-125% bound indicating comparable bioavailability between both test products. Both test products were generally well-tolerated with no serious AEs reported.
The bioavailability of a single 7.5 mL dose of AMPH EROS 2.5 mg/mL was comparable to a single 30 mg capsule dose of ER MAS. AMPH EROS (both d- and l-amphetamine) showed equivalent peak and overall exposure to ER MAS under fasted conditions.
Tris Pharma, Inc.
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
Attention-deficit/hyperactivity disorder (ADHD) is a neurobehavioral disorder characterized by pervasive impairment in symptoms of inattention, hyperactivity, and impulsivity. Psychopharmacologic ...treatment is targeted at the management of symptoms of ADHD, and evidence exists that ADHD persists into adulthood. Clinical practice guidelines recommend a combination of behavior therapy and psychostimulant medication for the treatment of ADHD in children, adolescents, and adults. Psychostimulants are often prescribed for ADHD in adults, and amphetamine long has been considered a mainstay of treatment for this population. As adult patients seek relief from ADHD symptoms early in the workday and into the early evening hours, with fewer required doses, extended-release formulations with an early onset of efficacy and an extended duration of effect are considered very desirable. The amphetamine-extended release tablet (AMPH ER TAB) was developed to provide a portable, easy-to-use amphetamine tablet dosage option that can be chewed or swallowed whole.
To evaluate the efficacy and safety of an Amphetamine Extended-Release Tablet (AMPH ER TAB) in adults with ADHD aged 18 to 60 years. Methods: In a 5-week forced dose-titration phase, eligible subjects were randomized to either oral double-blind AMPH ER TAB 5 mg starting dose or matching placebo, once daily in the morning beginning the day after the Baseline Visit. Subjects were titrated up (5 mg increments) each week. Safety and efficacy assessments were done weekly. After Visit 3, subjects received 20 mg for 14 (3) days before Visit 5 (V5). Subjects who could not tolerate study drugs discontinued. A Permanent Product Measure of Performance (PERMP) placement test was done at Screening or Baseline. At V5, efficacy assessments included the administration of serial PERMPs predose, 0.5, 1, 2, 4, 8, 10, 12, 13, and 14 hours postdose. The primary efficacy endpoint was the mean PERMP-T score across postdose time points during the Visit 5 serial PERMPs. Safety was monitored by AEs assessed at each visit, C-SSRS, vital signs, weight, and assessment of sleep, appetite, mood, and psychotic AEs.
The mean postdose PERMP-T score over all postdose time points at V5 was statistically significantly higher in the AMPH ER TAB group vs placebo (302.8 vs 279.6; P = .0043). Common adverse events were decreased appetite, insomnia, and dry mouth. The majority of TEAEs were mild to moderate in severity, and no SAEs were reported.
The AMPH ER TAB demonstrated efficacy in the treatment of symptoms of ADHD in adults, with an anticipated safety profile.
Tris Pharma, Inc.
This Phase 1, open-label, single-dose, one-period, one-treatment PK study enrolled 12 children 6-12 y with ADHD. PK parameters for d- and l-amphetamine in plasma (Cmax, tmax, AUC0-8, and t1/2) were ...calculated and expressed as means, geometric means, and standard deviations. The primary endpoint was all objective PK measurements at 28 hours post-dose. PK was evaluated for 2 cohorts (6 pts ages 6-9 y and 6 pts aged 10-12 y). Safety was monitored continuously and assessed based on occurrence of adverse events.
A single dose of 10 mg (4 ml) AMPH EROS (2.5 mg/ml) administered under fasted conditions resulted in a rapid rise in mean plasma concentration in d-amphetamine, reaching maximum concentrations within 5 hours. The overall study population mean (SD) plasma AUC0-8 (d-amphetamine) was 1061.2 (309) h*ng/mL, and for l-amphetamine was 380.5 (112) h*ng/mL. The mean maximum concentration (Cmax) for the overall study population was 54.91 ng/mL and 17.1 (5.2) ng/mL for d- and l-amphetamine, respectively. The overall study population median time to maximum concentrations (Tmax) for d-amphetamine were reached at 3.4 hours, and for l-amphetamine at 4.1 hours. The elimination half-life (t1/2) for the entire study cohort was 10.6 (2.0) hours for d-amphetamine, and 12.5 (3.2) hours for l-amphetamine. Directionally, a higher mean Cmax, AUC0-8, AUCt, and median Tmax were observed in the younger (6 to 9-year-old) age group, and this result was consistent with both the d- and l-amphetamine enantiomers. The mean elimination t1/2 for both d- and l-amphetamine was higher in the older cohort (10-12 years) than in the 6 to 12-year-olds. Study drug was well-tolerated by the subjects in this study. Two TEAEs were reported in one subject TEAEs (diarrhea and rash on legs) occurred approximately 12 hours postdose.
This study confirmed that the PK profile of AMPH EROS in 6 to 12-year-olds provided a consistent, predictable extended-release profile in a highly titratable liquid formulation, and this finding was relatively consistent and directionally predictable between the age groups assessed, with higher maximum concentrations and AUCs and shorter elimination half-lives noted in the younger population, with no anomalous parameters demonstrated, and no untoward or unexpected safety issues noted.
Tris Pharma, Inc.
ADHD is, for many people, a lifelong disease that requires chronic medication use. Stimulant therapy is often recommended as first-line treatment for ADHD. Adherence to stimulant treatment among ...patients diagnosed with ADHD is poor. Major regulatory agencies have recommended measurement of palatability for new tablet formulations. A new amphetamine extended-release tablet (AMPH ER TAB) for the treatment of attention-deficit/hyperactivity disorder (ADHD) was developed. The AMPH ER TAB has a bubblegum flavor and can be chewed or swallowed whole. In 2016, the FDA developed a draft guidance document on the topic of chewable drug tablet formulation palatability.
A palatability study of the AMPH ER TAB using the 2016 FDA guidance was conducted. Subjects were asked to assess the taste, aftertaste, and mouthfeel of the tablet formulation using a short questionnaire. Scores from the questionnaire were rated and presented.
The substudy assessed 35 subjects with a mean age of 38 (±11) years. Subjects were predominantly male, non-Hispanic, and White. Most subjects rated the oral sensation/mouth feel and taste of the tablet as positive (pleasant to very pleasant) (70.1% and 83.6%, respectively). Additionally, 86.6% of the subjects rated the strength of the taste as neutral (moderate taste) or positive (mild to no taste). Finally, 82.1% of all subjects rated the aftertaste as positive (pleasant to very pleasant) and 92.5% of subjects rated the strength of the aftertaste as neutral or positive (mild to no taste). The trends in evaluation scores for each question were similar regardless of whether the ER chewable tablet was administered under fasted or fed conditions.
The positive palatability data presented here will be useful for future "real-world" assessments of adherence to treatment with the AMPH ER TAB. Enhanced adherence may bolster the argument that taste, mouthfeel, and aftertaste are critical determinants of treatment adherence.
Rapid diagnosis and management of AMI have great impact on morbidity and mortality. Diagnosis which is based on elevation of cardiac biomarkers has its limitations. Copeptin is the C-terminal part of ...the vasopressin prohormone. The pathophysiology mode of release should theoretically add diagnostic information of cardiac cell necrosis. One of the major limitations of cardiac biomarkers is the delayed release in circulation. So looking for a new marker with a short diagnostic time window is needed. Aim is to determine the role of copeptin as an early marker for acute non-ST elevation MI (NSTEMI). This study included 88 patients with chest pain. They were divided into 2 groups. Group (1); included 30 patients with diagnosis of NSTEMI. Diagnosis of AMI was established according to the universal definition of MI. Group (2); included 58 patients with diagnosis of unstable angina (UA). Full medical history, physical examination, 12 lead ECG, random blood glucose level, renal function, total cholesterol, triglyceride, cardiac troponin I and Copeptin were obtained on admission. Follow up cardiac troponin I was done. Inclusion criteria: Defined as chest pain of ⩽6h duration since onset, suggestive of myocardial ischemia, and lasting >20min. at rest. Exclusion criteria: Patients with positive First cardiac troponin were rolled out, patients with ST segment elevation were rolled out. Other exclusion criteria: Patients presenting after a cardiac arrest, Trauma or major surgery within the last 4 week; pregnancy; IV drug abuse; age less than 18 years; shock and sepsis. Patients who were included had second troponin I re- done and copeptin analysis done. In group 1 (NSTEMI) 28 patients had ECG changes and only 2 had NSTEMI without ECG changes. In group 2 (UA) 23 patients had ECG changes and 35 patients had normal ECG. Males and females were 49 and 39. Age in G1 and G2 was 60±4 and 53±5. Copeptin analysis was done 6h after Infarction or chest pain. All the patients with NSTEMI (30) had positive copeptin and positive troponin except one only who had+troponin only and another one who had + copeptin only. Of the 58 patients without MI none had the two tests positive, only one had+troponin and one had+copeptin. Using ROC curve: copeptin had sensitivity 100% and specificity 82.8% with using cut off point 13.2pmol/l. So copeptin can be used for early detection of myocardial infarction. Copeptin seems to be an ideal confirmatory marker for rapid rule out of AMI. If the two tests (with troponin) are positive, this is evident MI; if the two are negative it rules out MI.
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