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.

A Single-Dose, Two-Way Crossover, Open-Label Bioequivalence Study of an Amphetamine Extended-Release Oral Suspension in Healthy Adults.

Objective: The purpose of this study was to compare the pharmacokinetics of a new extended-release amphetamine oral suspension (AMP XR-OS) with a standard extended-release mixed amphetamine salts product, Adderall XR®. Method: In this single-dose, open-label, randomized, two-period, two-treatment crossover study, 42 healthy adult volunteers received 15 mL of AMP XR-OS in one period and a 30 mg Adderall XR capsule in another period (both containing 18.8 mg of amphetamine base) under fasted conditions. Blood samples were analyzed for d- and l-amphetamine concentrations, and pharmacokinetic parameters Cmax, AUC0-5, AUC5-last, and AUCinf were calculated to determine bioequivalence. Safety was monitored throughout the study. Results: The 90% confidence intervals (CIs) for the log-transformed Cmax, AUC0-5, AUC5-last, and AUCinf fell within the accepted 80% to 125% range for establishing bioequivalence for d- and l-amphetamine. The most common adverse events were nausea and decreased appetite. Conclusion: AMP XR-OS is bioequivalent to Adderall XR in healthy adult participants.

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.

A Comparison of the Pharmacokinetics of Methylphenidate Extended-Release Orally Disintegrating Tablets With a Reference Extended-Release Formulation of Methylphenidate in Healthy Adults.

Extended-release (ER) methylphenidate (MPH) is a first-line treatment for attention-deficit/hyperactivity disorder. A methylphenidate extended-release orally disintegrating tablet (MPH XR-ODT) has recently been developed. This was a randomized, open-label, 3-period, 3-treatment study comparing the bioavailability and absorption of 2 MPH XR-ODT formulations with an MPH ER reference medication. Here we report the 2 treatments comparing the commercial MPH XR-ODT formulation and reference medication. Following a ≥10-hour fast, 42 healthy adults received 60 mg of reference medication or MPH XR-ODT (2 × 30 mg). The following pharmacokinetic (PK) parameters were calculated for total methylphenidate (d + l): maximum plasma concentration (Cmax ), time to maximum plasma concentration (Tmax ), terminal half-life (T1/2 ), and areas under the concentration-time curve from time zero to the time of the last quantifiable concentration (AUClast ), and from time zero extrapolated to infinity (AUCinf ). Secondary PK end points included partial AUCs. Safety was also assessed. Overall systemic exposure to methylphenidate after MPH XR-ODT administration was similar to that of the reference product, and the concentration-time profiles for MPH XR-ODT and the reference drug were similar, although the Cmax was 25% higher for MPH XR-ODT. The most common treatment-emergent adverse events were nausea (6) and anxiety (4), which were similar across treatments.

Pharmacokinetics of a New Amphetamine Extended-release Oral Liquid Suspension Under Fasted and Fed Conditions in Healthy Adults: A Randomized, Open-label, Single-dose, 3-treatment Study.

PURPOSE: A new amphetamine extended-release liquid formulation (AMP XR-OS), intended for the treatment of attention-deficit/hyperactivity disorder, has been developed. This study was performed to determine if administration with food affected the rate of absorption or bioavailability of AMP XR-OS. The formulation was also compared with an equivalent dose of an extended-release mixed amphetamine salts reference product (30 mg) under fed conditions. METHODS: Thirty adult volunteers participated in this single-dose, open-label, randomized, 3-period, 3-treatment crossover study. Each participant received a single 15-mL dose of AMP XR-OS (equivalent to 30 mg of the reference drug) under fasted conditions, a single 15-mL dose of AMP XR-OS under fed conditions, and a single dose of the reference drug under fed conditions. A 7-day washout separated the 3 treatment periods. Blood samples were collected at predetermined time points and analyzed for d- and l-amphetamine. Pharmacokinetic parameters reported are AUC0-5, AUC0-last, AUC5-last, and AUC0-∞; Cmax; elimination t1/2; and Tmax. The geometric mean ratios and 90% CIs of Cmax, AUC0-last, and AUC0-∞were determined for the comparison of AMP XR-OS fed and fasted, and Cmax, AUC0-5, AUC5-last, and AUC0-∞ were calculated for AMP XR-OS compared with the reference drug under fed conditions. Safety was also assessed. FINDINGS: Twenty-nine subjects completed the study. Subjects were mostly male, white, and of Hispanic/Latino ethnicity with a mean age of 35.83 years and a mean BMI of 25.36kg/m2. The 90% CIs of Cmax, AUC0-last, and AUC0-∞ for AMP XR-OS fasted versus fed were within the accepted 80% to 125% range, indicating lack of a food effect. In the comparison of AMP XR-OS fed versus the reference product, Cmax, AUC5-last, and AUC0-∞ were within the range to establish bioequivalence; however, AUC0-5 was significantly higher for AMP XR-OS compared with that of the reference drug. This difference between products was likely due to the known delay of Tmax and decreased exposure when the extended-release mixed amphetamine salts reference product is administered with food. A total of 36 mild or moderate adverse events were reported; 1 subject withdrew due to an adverse event, and no deaths occurred. These adverse events were consistent with the known pharmacodynamic effects of amphetamine. IMPLICATIONS: The absence of a food effect may allow for AMP XR-OS to be administered with or without a meal.

Pharmacokinetics of a Novel Amphetamine Extended-Release Orally Disintegrating Tablet in Children with Attention-Deficit/Hyperactivity Disorder.

BACKGROUND: A novel formulation for treating attention-deficit/hyperactivity disorder (ADHD) has recently been developed-amphetamine extended-release orally disintegrating tablets (AMP XR-ODTs). In this study, we assessed the rate of absorption and exposure of AMP XR-ODT under fasted conditions in children with ADHD. METHODS: Children (6-12 years) with ADHD were enrolled in a single-dose, open-label, single-period pharmacokinetic (PK) study. Patients were stratified by age (6-7, 8-9, and 10-12 year olds) and were dosed with 18.8-mg AMP XR-ODT under fasted conditions. Plasma samples were analyzed for d-and l-amphetamine. Maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), area under the concentration-time curve from time zero-infinity (AUCinf), weight-normalized clearance (CL/F), and weight-normalized volume of distribution (Vz/F) were assessed. The geometric mean and 95% confidence intervals (CIs) were calculated for weight-normalized CL/F and Vz/F in each age group to determine if the 95% CIs were within the target range of 60%-140%. RESULTS: A total of 28 children completed the study. The 95% CIs for the geometric mean CL/F/kg and Vz/F/kg for both d- and l-amphetamine fell within the target range of 60%-140% for each age group, thus meeting the primary end point. Four participants experienced treatment-related adverse events, including vomiting (n = 3), abdominal pain (n = 2), dry mouth (n = 1), and insomnia (n = 1). CONCLUSIONS: AMP XR-ODT, a novel formulation that does not require swallowing an intact tablet or capsule, was well tolerated and demonstrated a PK profile consistent with once-daily dosing in children with ADHD.

A randomized crossover study to assess the pharmacokinetics of a novel amphetamine extended-release orally disintegrating tablet in healthy adults.

OBJECTIVES: In this pharmacokinetic (PK) study in healthy adults, we sought to: (1) compare the PK properties of a novel amphetamine extended-release orally disintegrating tablet formulation (Adzenys XR-ODT™ [AMP XR-ODT]) to a reference extended-release mixed amphetamine salts (MAS ER) formulation and (2) assess the effect of food on AMP XR-ODT. METHODS: Forty-two adults were enrolled in a single-dose, open-label, 3-period, 3-treatment, randomized crossover study and received an 18.8-mg dose of AMP XR-ODT (fasted or fed) or equivalent dose (30 mg) of MAS ER (fasted). Plasma samples were analyzed for d-and l-amphetamine. Maximum plasma concentration (Cmax), time to maximum plasma concentration (Tmax), elimination half-life (T1/2), area under the concentration-time curve from time zero to last quantifiable concentration (AUClast), from time zero to infinity (AUCinf), relevant partial AUCs, and weight-normalized clearance (CL/F/kg) were assessed. The PK parameters were compared across treatments using an ANOVA. Safety was also assessed. RESULTS: A total of 39 adults completed this study. The geometric mean ratios (90% confidence interval [CI]) for AMP XR-ODT/MAS ER Cmax, AUC5-last, AUClast, and AUCinf were within 80%-125% for both d-and l-amphetamine. The 90% CIs for AUC0-5 were slightly below the 80%-125% range. When AMP XR-ODT was administered with food, there was a slight decrease in the d-and l-amphetamine Cmax and approximately a 2-hour delay in Tmax. The most common adverse events reported (>5% of participants) were dry mouth, palpitations, nausea, dizziness, headache, anxiety, and nasal congestion. CONCLUSIONS: AMP XR-ODT displayed a PK profile similar to MAS ER, and no clinically relevant food effect was observed.