Lisdexamfetamine dimesylate: linear dose-proportionality, low intersubject and intrasubject variability, and safety in an open-label single-dose pharmacokinetic study in healthy adult volunteers

• Published in: Journal of clinical pharmacology Vol. 50; no. 9; p. 1001
• Main Authors: Ermer, James, Homolka, Robert, Martin, Patrick, Buckwalter, Mary, Purkayastha, Jaideep, Roesch, Benno
• Format: Journal Article
• Language: English
• Published: England 01.09.2010
• Subjects: Adult; Area Under Curve; Attention Deficit Disorder with Hyperactivity - drug therapy; Blood Pressure - drug effects; Central Nervous System Stimulants - adverse effects; Central Nervous System Stimulants - blood; Central Nervous System Stimulants - pharmacokinetics; Central Nervous System Stimulants - pharmacology; Dextroamphetamine - adverse effects; Dextroamphetamine - blood; Dextroamphetamine - pharmacokinetics; Dextroamphetamine - pharmacology; Dose-Response Relationship, Drug; Electrocardiography - drug effects; Female; Headache - chemically induced; Humans; Lisdexamfetamine Dimesylate; Male; Middle Aged; Prodrugs - adverse effects; Prodrugs - metabolism; Prodrugs - pharmacokinetics; Prodrugs - pharmacology; Pulse; Young Adult
• ISSN: 1552-4604
• DOI: 10.1177/0091270009357346

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 (C(max)) and area under the concentration-time curve from time 0 to infinity (AUC(0-∞)) increased linearly and dose-dependently for d-amphetamine. Median time to C(max) 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 (<20%) for both C(max) and AUC(0-∞). Adverse events included nausea, dizziness, headache, psychomotor hyperactivity, and dysuria. These findings indicate that the pharmacokinetic parameters of d-amphetamine were dose-proportional and predictable over a wide range of lisdexamfetamine dimesylate doses.