Open-Label Dose Optimization of Methylphenidate Extended-Release Orally Disintegrating Tablet in a Laboratory Classroom Study of Children with Attention-Deficit/Hyperactivity Disorder.

Objective: To examine the efficacy, safety, and tolerability of methylphenidate extended-release orally disintegrating tablets (MPH XR-ODT) for the treatment of attention-deficit/hyperactivity disorder (ADHD) during the open-label dose-optimization/stabilization period of a phase 3 laboratory classroom study. Methods: Children (6-12 years) diagnosed with ADHD were enrolled. Treatment was initiated with MPH XR-ODT 20 mg daily. Doses were adjusted weekly by 10-20 mg during the 4-week dose-optimization period (visits 2-5) until an optimal dose was reached. The optimal dose was sustained during a 1-week stabilization period (visits 6-7). Efficacy was assessed using the ADHD Rating Scale-IV (ADHD-RS-IV) score and the Clinical Global Impression-Improvement (CGI-I) score. Adverse events (AEs) were recorded throughout the study. A secondary subgroup analysis by baseline ADHD-RS-IV score, sex, age, and weight was also performed. Results: The mean (standard deviation [SD]) final optimized MPH XR-ODT daily dose was 41.8 (14.6) mg and ranged from 20 to 60 mg. Final optimized dose was higher for children with more severe baseline ADHD-RS-IV total scores. ADHD-RS-IV total scores decreased progressively during dose optimization, with a mean (SD) change from baseline at visit 7 of -21.4 (8.9). CGI-I scores shifted from "minimally improved" (mean [SD]: 3.1 [1.1]) at visit 3 to "much improved" (1.6 [0.6]) at visit 7. Baseline ADHD-RS-IV total score was highest for participants optimized to 40 mg (mean [standard error]: 40.0 [1.4]) and lowest for those optimized to 20 mg (34.8 [2.1]). By visit 6, mean ADHD-RS-IV score was comparable for all optimized dose groups. Common treatment-emergent AEs (≥5% of participants) included decreased appetite, upper abdominal pain, headaches, and insomnia. Conclusions: Dose optimization of MPH XR-ODT led to a reduction in ADHD symptoms, indicated by a decrease in ADHD-RS-IV and CGI-I scores. AEs were consistent with those of other MPH products. Clinical Trial Registry: NCT01835548 (ClinicalTrials.gov).

An Open-Label, Multicenter, Single-Dose Pharmacokinetic Study of a Novel Amphetamine Extended-Release Orally Disintegrating Tablet in Preschool-Aged Children.

Objective: In the U.S. ∼33% of children with attention-deficit/hyperactivity disorder (ADHD) are diagnosed during their preschool years (<6 years of age). The majority of these children are treated with a psychopharmacological treatment, despite limited data on pharmacokinetics (PKs), efficacy, or safety of these medications in this population. A phase 4, single-dose open-label study was conducted to assess the PK profile of amphetamine extended-release orally disintegrating tablets (AMP XR-ODT) under fasted conditions in preschool-aged children with ADHD. Methods: Preschool-aged children (aged 4 to <6 years) with a confirmed ADHD diagnosis were enrolled and administered AMP XR-ODT 3.1 mg under fasted conditions. Plasma samples were analyzed for d- and l-amphetamine (AMP) via liquid chromatography-tandem mass spectrometry. Area under the concentration-time curve from time 0 extrapolated to infinity (AUC0-inf), area under the concentration-time curve from time 0 to the last measurable plasma concentration (AUC0-T), maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), terminal half-life (t1/2), apparent volume of distribution (Vz/F), and apparent clearance (CL/F) for d- and l-AMP and safety were assessed. Results: The PK and safety analyses included 15 preschool-aged children (4 years old, n = 6; 5 years old, n = 9); 14 completed the study. Quantifiable plasma concentrations for d- and l-AMP were observed 1.5 hours postdose and throughout the 24-hour sampling period. For d- and l-AMP, mean AUC0-inf was 315.2 and 104.4 h·ng/mL, AUC0-T was 296.0 and 96.8 h·ng/mL, t1/2 was 8.0 and 9.2 hours, Cmax was 23.0 and 7.0 ng/mL, Tmax was 3.9 and 4.0 hours, CL/F was 6996.3 and 6837.1 mL/h, and Vz/F was 75,874.5 and 84,140.0 mL, respectively. Adverse events included tachycardia (n = 2), neutropenia (n = 1), increased alanine aminotransferase (n = 1), and aspartate aminotransferase (n = 1). Conclusions: AMP XR-ODT 3.1 mg was well tolerated in preschool-aged children, with detectable plasma AMP concentrations over 24 hours, and a PK profile consistent with once-daily dosing.

Population Pharmacokinetic-Pharmacodynamic Modeling of a Novel Methylphenidate Extended-Release Orally Disintegrating Tablet in Pediatric Patients With Attention-Deficit/Hyperactivity Disorder.

PURPOSE/BACKGROUND: A methylphenidate (MPH) extended-release orally disintegrating tablet (MPH XR-ODT) formulation was recently approved for attention-deficit/hyperactivity disorder treatment in children 6 to 17 years of age. This analysis sought to develop a population pharmacokinetic (PK)/pharmacodynamic (PD) model to describe MPH XR-ODT PD-response data in a classroom study and use the model to simulate PD responses for a range of body weights and doses. METHODS/PROCEDURES: The MPH XR-ODT PK/PD model was developed with pediatric and adult PK data from prior studies and efficacy data from a laboratory classroom study in children with attention-deficit/hyperactivity disorder. In these studies, the safety profile of MPH XR-ODT was consistent with other extended-release MPH formulations. The PK/PD model efficacy end point was the Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale Combined score. Body weight effects on MPH clearance and volume of distribution were included in the resulting model. Simulations using the PK/PD model were performed for patients with body weights between 7 and 100 kg and MPH XR-ODT doses of 10 to 60 mg MPH hydrochloride equivalents. FINDINGS/RESULTS: In the PK/PD model, the maximal reduction in the Swanson, Kotkin, Agler, M-Flynn, and Pelham Scale Combined score was approximately 38 units, and the MPH concentration required to achieve 50% of the maximal reduction was 14.24 ng/mL, suggesting favorable efficacy for MPH XR-ODT. Simulations showed a direct correlation between the effective MPH XR-ODT dose and body weight, with heavier participants requiring higher doses for symptom control. IMPLICATIONS/CONCLUSION: This model may help facilitate the dose-titration process by identifying an effective MPH XR-ODT target dose.

Pharmacokinetics of a New Amphetamine Extended-Release Oral Suspension in Children with Attention-Deficit/Hyperactivity Disorder.

OBJECTIVE: An extended-release amphetamine (AMP) oral suspension has been developed to facilitate medication ingestion and dose titration. This study sought to determine the pharmacokinetic (PK) profile of this new formulation in children with attention-deficit/hyperactivity disorder (ADHD). METHODS: This was an open-label, single-period, PK study in 29 pediatric participants with ADHD. Participants were stratified into age groups 1 (6-7 years), 2 (8-9 years), and 3 (10-12 years), and dosed with 15 mL extended-release AMP liquid suspension (equivalent to 30 mg mixed AMP salts) after an overnight fast. Blood samples were collected at prespecified time points and analyzed for d- and l-AMP concentrations. Key PK parameters included maximum plasma concentration (Cmax), time to maximum plasma concentration, half-life (T1/2), area under the curve from time 0 to last quantifiable concentration (AUClast) and to infinity (AUCinf), oral clearance (CL/F), and volume of distribution (Vz/F). The 95% confidence intervals (CIs) about the geometric means of the weight-normalized CL/F, Vz/F, and AUClast were determined. Safety was also assessed. RESULTS: All participants completed the study. As age increased, mean maximum and total exposure to AMP decreased; weight-normalized CL/F slightly increased, resulting in decreasing T1/2 values with age. For d- and l-AMP, the 95% CIs for the geometric means of weight-normalized CL/F/kg and Vz/F/kg were within the 60%-140% range for groups 2 and 3, while those of weight-normalized AUClast were within range for all age groups. Adverse events were mild and consistent with the safety profile of AMP. CONCLUSIONS: Exposure (Cmax, AUCinf, and AUClast) to AMP decreased with age, possibly as a result of the 30-mg/15-mL fixed dose across a range of weights (20-57 kg) and the consequent lower dose per kilogram in older participants, as well as the slight increase in clearance with age.

Efficacy, Safety, and Tolerability of an Extended-Release Orally Disintegrating Methylphenidate Tablet in Children 6-12 Years of Age with Attention-Deficit/Hyperactivity Disorder in the Laboratory Classroom Setting.

OBJECTIVE: Methylphenidate extended-release orally disintegrating tablets (MPH XR-ODTs) represent a new technology for MPH delivery. ODTs disintegrate in the mouth without water and provide a pharmacokinetic profile that is consistent with once-daily dosing. This study sought to determine the efficacy, safety, and tolerability of this novel MPH XR-ODT formulation in school-age children with attention-deficit/hyperactivity disorder (ADHD) in a laboratory classroom setting. METHODS: Children aged 6-12 years with ADHD (n = 87) were enrolled in this randomized, multicenter, double-blind, placebo-controlled, parallel, laboratory classroom study. The MPH XR-ODT dose was titrated to an optimized dose during a 4-week open-label period and maintained on that dose for 1 week. Participants (n = 85) were then randomized to receive their optimized dose of MPH XR-ODT or placebo once daily for 1 week (double blind), culminating in a laboratory classroom testing day. Efficacy was evaluated using the Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Attention, Deportment, and Combined scores along with Permanent Product Measure of Performance (PERMP; Attempted and Correct) assessments. Onset and duration of drug action were also evaluated as key secondary endpoints. Safety assessments included adverse events (AEs), physical examinations, electrocardiograms (ECGs), and the Columbia Suicide Severity Rating Scale (C-SSRS). RESULTS: The average SKAMP-Combined score on the classroom study day was significantly better for the MPH XR-ODT group (n = 43) than for the placebo group (n = 39; p < 0.0001). The effect was evident at 1 hour and lasted through 12 hours postdose. The average SKAMP-Attention, SKAMP-Deportment, PERMP-A, and PERMP-C scores were indicative of significantly greater ADHD symptom control for the MPH XR-ODT group. The most common AEs reported were decreased appetite, upper abdominal pain, headache, insomnia, upper respiratory tract infection, affect lability, irritability, cough, and vomiting. CONCLUSIONS: MPH XR-ODT was effective and well tolerated for the treatment of children with ADHD in a laboratory classroom setting. Clinical Trial Registry: NCT01835548 ( ClinicalTrials.gov ).

Randomized, double-blind comparison of sertraline and placebo for posttraumatic stress disorder in a Department of Veterans Affairs setting.

OBJECTIVE: To evaluate the efficacy of sertraline in the treatment of posttraumatic stress disorder (PTSD) in a Veterans Affairs (VA) clinic setting involving patients with predominantly combat-related PTSD. METHOD: 169 outpatient subjects with a DSM-III-R diagnosis of PTSD and who scored 50 or higher on Part 2 of the Clinician-Administered PTSD Scale (CAPS-2) at the end of a 1-week placebo run-in period participated. Patients recruited from 10 VA medical centers were randomly assigned to 12 weeks of flexibly dosed sertraline (25-200 mg/day) (N = 86; 70% with combat-related PTSD; 79% male) or placebo (N = 83; 72% combat-related PTSD; 81% male) between May 1994 and September 1996. The primary efficacy measures were the mean change in CAPS-2 total severity score from baseline to endpoint, in the total score from the Impact of Event Scale, and in the Clinical Global Impressions-Severity of Illness and Improvement scales. RESULTS: There were no significant differences between sertraline and placebo on any of the primary or secondary efficacy measures at endpoint. In order to understand the results, gender, duration of illness, severity of illness, type of trauma, and history of alcohol/substance abuse were explored as potential moderators of outcome, but no consistent effects were uncovered. Sertraline was well tolerated, with 13% of patients discontinuing due to adverse events. CONCLUSION: Sertraline was not demonstrated to be efficacious in the treatment of PTSD in the VA clinic settings studied.

Eletriptan in migraine patients reporting unsatisfactory response to rizatriptan.

OBJECTIVE: The objective of this open-label study was to evaluate the efficacy of switching patients who had a previous unsatisfactory response to rizatriptan to eletriptan 40 mg. Background.-The characteristics of individual migraine patients can vary tremendously and can have a significant impact on treatment outcomes. In addition, clinical experience has demonstrated that the triptans are not identical or interchangeable and that patients who respond poorly or who are dissatisfied with one agent can derive benefit by being switched to another agent within the triptan class. METHODS: Patients were eligible if they met International Headache Society criteria for migraine, with a frequency of 1 to 6 migraine attacks per month, and had documented "unsatisfactory treatment response" to rizatriptan within the past year (54% on the melt formulation; 46% on tablets). Reasons for dissatisfaction with rizatriptan (>1 could be cited) included inadequate (84%) or slow onset (50%) of pain relief, high recurrence rate (69%), and lack of improvement in associated symptoms (60%). One hundred twenty-three patients were eligible for treatment. Patients were instructed to take eletriptan 40 mg as soon as they were certain that their headache was a migraine, regardless of level of pain severity (8% treated headaches that were mild). RESULTS: Headache response at 2 hours (first-attack data) was 64%. Absence of nausea (from baseline to 2 hours) increased from 50% to 78%, absence of photophobia from 30% to 72%, and absence of phonophobia from 39% to 77%. Functional response at 2 hours was 63%, with 41% of patients reporting normal functioning. Treatment with eletriptan 40 mg was associated with a 27% to 40% reduction in migraine attack-related functional impairment, as measured by the PQ-7. Recurrence rates were 36.6%. Overall, 72% of patients rated eletriptan as a "good-to-excellent" treatment, and 78% reported overall satisfaction with the degree of headache relief. CONCLUSION: The results of this study suggest that eletriptan is an efficacious treatment option for patients who are dissatisfied with their response to rizatriptan.

In vivo disintegration profiles of encapsulated and nonencapsulated sumatriptan: gamma scintigraphy in healthy volunteers.

The goal of this exploratory pilot study was to use gamma scintigraphy to evaluate, under physiological conditions, disintegration profiles of encapsulated and nonencapsulated formulations of 100 mg sumatriptan. Using a crossover design, healthy volunteers (n = 10) ingested 100-mg doses of sumatriptan tablets radiolabeled with 111Indium, as well as encapsulated sumatriptan tablets that were prepared similarly, then placed within a gelatin capsule and backfilled with an excipient blend radiolabeled with 99mTechnetium. A gamma camera recorded scintigraphic images until 5 hours postdose. Initial disintegration of the gelatin capsule was observed at a mean (range) of 5 minutes (1-11 minutes); disintegration was complete within 14 minutes (5-24 minutes). For nonencapsulated versus encapsulated tablets, the mean (+/- standard deviation) time to initial disintegration (6 +/- 5 minutes vs 8 +/- 5 minutes) and time to complete disintegration (18 +/- 14 minutes vs 16 +/- 7 minutes) were comparable. Results of this study demonstrate that encapsulated and nonencapsulated sumatriptan have equivalent in vivo dissolution rates.

Severe vascular events in migraine patients.

OBJECTIVE: To estimate rates of vascular events in relation to dispensing of triptans and ergot alkaloids among migraineurs, and to compare these rates with those of nonmigraineurs. CONTEXT: It has been speculated that the use of triptans or ergot alkaloid drugs might increase risk of ischemic events through vasoconstriction. DESIGN: A retrospective cohort study of 130,411 migraineurs and 130,411 age-, sex-, and health plan-matched nonmigraineurs who were members of UnitedHealthcare during 1995 through 1999. The data source for this study was Ingenix's research database containing pharmacy and medical claims for UnitedHealthcare members, and the National Death Index. MAIN OUTCOME MEASURES: Incidence of cardiovascular and cerebrovascular events and mortality. RESULTS: Migraineurs and nonmigraineurs had identical rates of myocardial infarction: 1.4 per 1000 person-years. Migraineurs were 67% more likely to suffer a stroke than nonmigraineurs (adjusted relative risk [RR] 1.67, 95% confidence interval [CI] 1.31-2.13), and had higher rates of unstable angina and transient ischemic attacks. There was no increase in risk of myocardial infarction with current (adjusted RR 0.80, 95% CI 0.58-1.11) or recent (adjusted RR 1.15, 95% CI 0.71-1.87) triptan use. Neither current (adjusted RR 0.90, 95% CI 0.64-1.26) nor recent (adjusted RR 0.84, 95% CI 0.46-1.55) triptan use was associated with risk of stroke. Current users of ergot alkaloids were somewhat more likely to have a stroke than other migraineurs (adjusted RR 1.49, 95% CI 0.93-2.41), but there was no dose-response relationship. CONCLUSIONS: Use of triptans is not associated with increased risk of any ischemic events, including myocardial infarction and stroke, or mortality. Consistent with previous studies, migraineurs in general have an elevated risk of stroke, but not myocardial infarction, compared with nonmigraineurs.

Comparative efficacy of eletriptan 40 mg versus sumatriptan 100 mg.

OBJECTIVE: To confirm the efficacy advantage of eletriptan 40 mg over sumatriptan 100 mg. Background.-Eletriptan 80 mg has demonstrated significantly greater efficacy when compared to both sumatriptan 50 mg and 100 mg in two studies. Eletriptan 40 mg demonstrated significantly greater efficacy than sumatriptan 100 mg in one previous trial. METHODS: Two thousand one hundred thirteen patients with a diagnosis of migraine according to International Headache Society criteria were randomized using a double-blind, double-dummy, parallel-group design, and treated for a single migraine attack with either eletriptan 40 mg, sumatriptan 100 mg, or placebo. The primary endpoint was 2-hour headache response. Secondary endpoints included headache response rates at 1 hour, pain-free rates, absence of associated symptoms, functional response at 1 and 2 hours, and sustained headache response. RESULTS: Headache response rates at 2 hours postdose were significantly higher for eletriptan 40 mg (67%) than for sumatriptan 100 mg (59%; P <.001) and placebo (26%; P <.0001). Eletriptan 40 mg consistently showed significant (P <.01) efficacy over sumatriptan 100 mg across secondary clinical outcomes, including 1-hour headache response; 2-hour pain-free response; absence of nausea, photophobia, and phonophobia; functional improvement; use of rescue medication; treatment acceptability; and sustained headache response (P <.05). Overall, treatment-related adverse events were low, nausea being the only adverse event with an incidence of 2% or higher (4.9% with eletriptan, 4.2% sumatriptan, 2.8% placebo). CONCLUSION: This trial confirmed that eletriptan 40 mg offers superior efficacy in treating migraine pain and associated symptoms and in restoring patient functioning when compared with sumatriptan 100 mg.