Pharmacokinetics of a Modified-Release Dexamphetamine Sulfate Formulation Following Single and Multiple Dosing in Healthy Adults: Comparative Bioavailability with Immediate-Release Dexamphetamine Sulfate, between Strengths, Assessment of Food and Meal Composition Effects.

Abstract

Background: A modified-release dexamphetamine sulfate formulation (DEX-MR) is under development for the treatment of attention-deficit/hyperactivity disorder.

Objective: We investigated the bioequivalence of once-daily DEX-MR to twice-daily immediate-release dexamphetamine sulfate (DEX-IR) after single and multiple dosing and between strengths, and effects of food and meal types.

Method: Three randomized, open-label, crossover studies in healthy males were conducted. In the single-dose study, participants received DEX-MR 20 mg, DEX-MR 10 mg (20 mg dose), and twice-daily DEX-IR 10 mg under fasted conditions and after a high-fat, high-calorie breakfast. In the breakfast study, participants received DEX-MR 20 mg and twice-daily DEX-IR 10 mg after a normocaloric and a high-fat, high-calorie breakfast. In the multiple-dose study, participants received DEX-MR 20 mg and twice-daily DEX-IR 10 mg for seven days each. In the run-in period (five days), participants consumed a normocaloric breakfast; on profile days, participants consumed a normocaloric breakfast (day 6) or a high-fat, high-calorie breakfast (day 7).

Results: Once-daily DEX-MR at a dose of 20 mg was bioequivalent to twice-daily DEX-IR 10 mg after single dosing under fasted and fed conditions and after multiple dosing under fed conditions. DEX-MR 10 mg and DEX-MR 20 mg were bioequivalent when administered as a single 20 mg dose. Food slightly reduced the rate and extent of absorption of DEX-MR and delayed the time to peak plasma concentration (t_max) by approximately two hours compared to the fasted state. Bioavailability of DEX-MR was comparable under different meal conditions (normocaloric vs. high-fat, high-calorie breakfast) both after single and multiple dosing.

Conclusions: Bioequivalence of once-daily DEX-MR and twice-daily DEX-IR was established. 1×2 DEX-MR 10 mg was bioequivalent to 1×1 DEX-MR 20 mg. DEX-MR should be administered with/after a meal to achieve the targeted pharmacokinetic profile (delayed t_max). Bioavailability of DEX-MR is not affected by meal composition (i.e., fat and caloric content).