A randomized, open-label, single-dose, three-treatment, three-period, crossover, phase I study was conducted to assess the pharmacokinetics of mixed amphetamine salts extended release (MAS XR) in adolescents with attention-deficit/hyperactivity disorder (ADHD).

Two cohorts of healthy adolescents 13–17 years of age with ADHD were enrolled in the study. Seventeen subjects, weighing ≤75 kg (≤ 65 lbs), were randomized to one of three dosing sequence groups (a single oral dose of MAS XR 10, 20, or 40 mg, follwed by crossover to the alternate treatments, with a 7-day washout between treatments). Six additional subjects, weighing >75 kg (>165 lbs), were randomized simihrly but received larger doses of MAS XR (20, 40, and 60 mg). Blood samples were collected before and at hours 1–12 after drug administration, as well as before and at hours 14, 24,48, and 60.

Linear pharmacokinetics of dextroamphetamine (D-amphetamine) and loamphetamine (L-amphetamine) were observed with MAS XR in both cohorts. The pharmacokinetics of D-amphetamine and L-amphetamine did not differ between male and female adolescents. A significant decrease in maximum exposure (Cmax) and increase in half-life were seen for both isomers with increasing age, but overall exposure (AUC∞ was not affected. Cmax and AUC∞ for both isomers decreased as body weight increased.

Exposure to MAS XR was linear and directly proportional to the dose administered in 13–17-year-old adolescents with ADHD. The time course of drug absorption and elimination did not appear to be affected by dose at 10–40 mg in subjects weighing ≤75 kg, and at 20–60 mg in subjects weighing >75 kg. Gender did not affect the pharmacokinetics of MAS XR; age and body weight influenced the profile of certain pharmacokinetic variables.

Assess long-term tolerability and efficacy of once-daily mixed amphetamine salts extended release (MAS XR) for attention-deficit/hyperactivity disorder (ADHD) in adolescents (13–17 years of age).

Efficacy of MAS XR (10–60 mg/day) in 138 adolescents with ADHD was assessed in a 6-month, openlabel, extension study following participation in a 4-week, randomized, placebo-controlled trial of MAS XR. Efficacy was based on ADHD Rating Scale-IV (ADHD-RS-IV) scores and Clinical Global Impressions-Improvement (CGI-I) ratings at end point. Tolerability was based on reported adverse events, physical and laboratory examintions, vital signs, and electrocardiographic measures.

Patients exhibited sustained improvement in ADHD symptoms in this 6-month, open-label study of MAS XR 10–60 mg/day. End point ADHD-RS-IV total score was significantly decreased from baseline (-7.9; P<.0001); similar decreases were seen for hyperactivity/impulsivity (-4.0; P<.0001) and indttentiveness (-3.8; P<.0001). Based on CGI-I ratings, 60.9% of patients were very much/much improved, 33.3% were unchanged, 5.8% were much worse, and 0% were very much worse. The most common adverse events related to MAS XR were anorexia (24.6%), weight loss (24.6%), headache (14.5%), and nervousness (13.0%).

Long-term MAS XR therapy is generally well tolerated and exerts sustained control of ADHD symptoms in otherwise healthy adolescents.

Assess cardiovascular effects of once-daily mixed amphetamine salts extended release (MAS XR) in adolescents (13–17 years of age) with attention-deficit/hyperactivity disorder (ADHD).

Blood pressure (BP), pulse, and electrocardiograms were assessed in 327 healthy subjects during a 4-week, randomized, double-blind, placebo-controlled, forced dose-titration study. Placebo (n=69) or once-daily MAS XR(10, 20, 30, or 40 mg) was administered to subjects ≤75 kg (n=233); 50- and 60-mg MAS XR was administered to subjects >75 kg (n=25). One hundred thirty-eight subjects participated in a 6-month, open-label extension study.

Changes in BP and QTcB (Bazett's formula) intervals at 4 weeks with MAS XR were not significantly different from the placebo group. Pulse increased by 5.0 and 8.5 bpm after 3 weeks with MAS XR 20 and 50 mg/day, respectively (P≤.002). After 6 months of open-label MAS XR treatment, mean increases in systolic BP (1.7 mm Hg; P=.0252) and pulse (4.4 bpm; P<.0001) were statistically, but not clinically, significant diastolic BP was not significantly changed (0.6 mm Hg) A decrease in QTcB interval (-4.6±19.9 msec) was statistically (P=.009), but not clinically, significant. There were no serious cardiovascular adverse events.

Cardiovascular effects of short- and long-term MAS XR treatment (≤60 mg/day) were minimal in otherwise healthy adolescents with ADHD.

Assess cardiovascular effects of mixed amphetamine salts extended release (MAS XR) in children and adolescents (6–17 years of age) with oppositional defiant disorder (ODD).

A 4-week, double-blind, randomized, placebo-controlled, forced dose-titration study of once-daily 10-, 20-, 30-, or 40-mg MAS XR (n=308). Resting/sitting systolic blood pressure (SBP) and diastolic blood pressure (DBP) and pulse were measured at baseline and weekly thereafter. Electrocardiograms (ECGs) were obtained at screening and study end point.

At study end point, mean changes in SBP and DBP were minimal with MAS XR (SBP: -0.2 to 1.1 mm Hg; DBP: -1.0 to 2.1 mm Hg) and comparable to placebo (SBP: -0.6 mm Hg; DBP: -0.4 mm Hg). Mean end point pulse was similar with MAS XR (80.6–84.7 bpm) and placebo (81.8 bpm). No dose-related trends in blood pressure and pulse changes were observed. No clinically significant changes in ECG parameters were seen with MAS XR. Changes in QTcB (Bazett's formula) interval with MAS XR were small (0.5 to 3.9 msec). No patient discontinued due to a cardiovascular adverse event.

Cardiovascular effects of MAS XR (10–40 mg) were minimal and comparable to those with placebo in children and adolescents with ODD.