Intranasal versus Oral Administration of Lisdexamfetamine Dimesylate

• Published in: Clinical drug investigation 2011-06, Vol.31 (6), p.357
• 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: Article
• Language: English
• ISSN: 1173-2563; 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 99mTc-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 (Cmax) and area under the plasma concentration-time curve from time zero to time of last measurable concentration (AUClast) 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 (tmax) for d-amphetamine: 5 hours for PO administration versus 4 hours for IN administration. Mean ± SD elimination half-life (t½) 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 simil