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

Abstract

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 AUC_0-5, AUC_0-last, AUC_5-last, and AUC_0-∞; C_max; elimination t_1/2; and T_max. The geometric mean ratios and 90% CIs of C_max, AUC_0-last, and AUC_0-∞were determined for the comparison of AMP XR-OS fed and fasted, and C_max, AUC_0-5, AUC_5-last, and AUC_0-∞ 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 C_max, AUC_0-last, and AUC_0-∞ 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, C_max, AUC_5-last, and AUC_0-∞ were within the range to establish bioequivalence; however, AUC_0-5 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 T_max 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.

Keywords: ADHD; amphetamine; drug delivery; food effect; pharmacokinetics; psychiatry.