Intranasal versus Oral Administration of Lisdexamfetamine Dimesylate A Randomized, Open-Label, Two-Period, Crossover, Single-Dose, Single-Centre Pharmacokinetic Study in Healthy Adult Men

• Published in: Clinical drug investigation Vol. 31; no. 6; pp. 357 - 370
• Main Authors: Ermer, James C., Dennis, Kerry, Haffey, Mary B., Doll, Walter J., Sandefer, Erik P., Buckwalter, Mary, Page, Richard C., Diehl, Brian, Martin, Patrick T.
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 01.06.2011; Wolters Kluwer Health, Inc
• Subjects: Administration, Intranasal; Administration, Oral; Adolescent; Adult; Attention-deficit hyperactivity disorder; Complications and side effects; Cross-Over Studies; Dextroamphetamine; Dextroamphetamine - administration & dosage; Dextroamphetamine - adverse effects; Dextroamphetamine - blood; Dextroamphetamine - pharmacokinetics; Dosage and administration; Drug therapy; Humans; Internal Medicine; Lisdexamfetamine Dimesylate; Male; Medicine; Medicine & Public Health; Middle Aged; Original Research Article; Patient outcomes; Pharmacokinetics; Pharmacology/Toxicology; Pharmacotherapy; Reference Values; Young Adult; United States; Abuse Liability; Pharmacokinetic Parameter; Lisdexamfetamine Dimesylate; Lisdexamfetamine; Maximum Observe Plasma Concentration
• ISSN: 1173-2563; 1179-1918; 1179-1918
• DOI: 10.2165/11588190-000000000-00000

Background and Objective : Data on pharmacokinetic parameters of the prodrug stimulant lisdexamfetamine dimesylate via alternate routes of administration are limited. The pharmacokinetics of d -amphetamine derived from lisdexamfetamine dimesylate after single oral (PO) versus intranasal (IN) administration of lisdexamfetamine dimesylate were compared. Methods : In this randomized, two-period, crossover study, healthy men without a history of substance abuse were administered single PO or IN (radiolabelled with ≤100 µCi 99m Tc-diethylenetriamine-pentaacetic acid and confirmed by scintigraphy) lisdexamfetamine dimesylate 50 mg ≥7 days apart. Serial blood samples were drawn to measure d -amphetamine and intact lisdexamfetamine at 0 (pre-dose), 15, 30 and 45 minutes and at 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post-dose for PO administration and at 0 (pre-dose), 5, 10, 15, 20, 30, 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 8, 12, 16, 24, 36, 48 and 72 hours post-dose for IN administration. Treatment-emergent adverse events (TEAEs) were assessed. Results : Eighteen subjects were enrolled and completed the study. The mean ± SD maximum observed plasma concentration (C max ) and area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUC last ) of d -amphetamine following PO administration of lisdexamfetamine dimesylate were 37.6 ± 4.54 ng/mL and 719.1 ± 157.05 ng · h/mL, respectively; after IN administration, these parameters were 35.9 ± 6.49 ng/mL and 690.5 ± 157.05 ng · h/mL, respectively. PO and IN administration demonstrated similar median time to reach C max (t max ) for d -amphetamine: 5 hours for PO administration versus 4 hours for IN administration. Mean ± SD elimination half-life (t 1/2 ) values were also similar for PO (11.6 ± 2.8 hours) and IN (11.3 ± 1.8 hours) lisdexamfetamine dimesylate. TEAEs after PO and IN administration were reported by 27.8% of subjects (5/18) and 38.9% of subjects (7/18), respectively; all AEs were mild or moderate in severity, and TEAEs such as anorexia, dry mouth, headache and nausea were consistent with known amphetamine effects. Conclusion : IN administration of lisdexamfetamine dimesylate resulted in d -amphetamine plasma concentrations and systemic exposure to d -amphetamine comparable to those seen with PO administration. Subject variability for d -amphetamine pharmacokinetic parameters was low. Both PO and IN lisdexamfetamine dimesylate demonstrated a tolerability profile similar to that of other long-acting stimulants.