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 (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.
Ermer
James
J
Shire Development, 725 Chesterbrook Blvd, Wayne, PA 19087, USA. jaermer@shire.com
Homolka
Robert
R
Martin
Patrick
P
Buckwalter
Mary
M
Purkayastha
Jaideep
J
Roesch
Benno
B
D000328:Adult; D019540:Area Under Curve; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy; D001794:Blood Pressure / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D003913:Dextroamphetamine / Q000009:adverse effects* / Q000097:blood / Q000493:pharmacokinetics* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006261:Headache / Q000139:chemically induced; D006801:Humans; D000069478:Lisdexamfetamine Dimesylate; D008297:Male; D008875:Middle Aged; D011355:Prodrugs / Q000009:adverse effects / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology; D011674:Pulse; D055815:Young Adult
D000697:Central Nervous System Stimulants; D011355:Prodrugs; D000069478:Lisdexamfetamine Dimesylate; D003913:Dextroamphetamine