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

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 mu Ci Tc-99m-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 circle h/mL, respectively; after IN administration, these parameters were 35.9 +/- 6.49 ng/mL and 690.5 +/- 157.05 ng circle 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.