Lisdexamfetamine Dimesylate: Linear Dose-Proportionality, Low Intersubject and Intrasubject Variability, and Safety in an Open-Label Single-Dose Pharmacokinetic Study in Healthy Adult Volunteers

The pharmacokinetics of lisdexamfetamine dimesylate, a long‐acting prodrug stimulant, and its active moiety, d‐amphetamine, including dose‐proportionality and variability, were assessed in 20 healthy adults. Subjects received a single dose, sequentially, of 50, 100, 150, 200, and 250 mg of lisdexamfetamine dimesylate. Plasma lisdexamfetamine dimesylate and d‐amphetamine were measured before dosing and 0.25 to 96 hours postdose. Dose‐proportionality and intersubject and intrasubject variability of pharmacokinetic parameters were examined. Safety assessments included adverse events. All 20 subjects received 50 and 100 mg while 18, 12, and 9 subjects received 150, 200, and 250 mg of lisdexamfetamine dimesylate, respectively. Ten subjects were discontinued during the study for prespecified stopping rules (2 consecutive hourly readings of blood pressure: systolic >160 mm Hg or diastolic >100 mm Hg). Mean maximum observed plasma concentration (Cmax) and area under the concentration—time curve from time 0 to infinity (AUC0‐∞) increased linearly and dose‐dependently for d‐amphetamine. Median time to Cmax ranged from 4 to 6 hours for d‐amphetamine and 1.0 to 1.5 hours for lisdexamfetamine dimesylate. Intersubject and intrasubject variability over doses from 50 to 150 mg was low (