(#5) Effect of External Heat Application on the Pharmacokinetics of d-Amphetamine Transdermal System and Comparison of Pharmacokinetics of d-Amphetamine Transdermal System With Oral Formulations

Abstract: Background: d-Amphetamine transdermal system (d-ATS) is a transdermal dextroamphetamine formulation approved for treating ADHD patients aged ?6 years. This study evaluates the effect of external heat on rate and extent of d-amphetamine absorption following d-ATS application and compares d-amphetamine pharmacokinetics (PK) following administration of d-ATS, oral extended-release amphetamine salts (amphetamine-ER), and oral lisdexamfetamine dimesylate. Methods: In an open-label cross-over study, healthy adults received d-ATS 5mg with/without heat in two-period Part 1 (n=14) or d-ATS 20mg, amphetamine-ER 30mg, and lisdexamfetamine 70mg in three-period Part 2 (n=18), with a seven-day washout between periods. PK were compared using a linear mixed-effects model. Results: With 9-hour 5mg d-ATS application, median T??? was 2h earlier and AUC???? 1.5-fold higher with heat than without. Geometric least-squares mean (GLSM) ratios (90% CI) for C??? and AUC????? with/without heat were 116% (109%, 124%) and 112% (104%, 120%), respectively. GLSM ratios for AUC????, C???, and AUC????? were 48%, 33%, and 21% lower, respectively, for d-ATS 20mg versus lisdexamfetamine. d-Amphetamine exposures with d-ATS were comparable to amphetamine-ER, except for AUC???? (GLSM ratio 23% lower for d-ATS). d-ATS was safe/well-tolerated, with no patch detachments. Conclusion: Transdermal drug delivery offers steady drug absorption and exposure with reduced plasma fluctuations. d-ATS provides d-amphetamine plasma concentrations for effective ADHD control at lower total daily doses than oral formulations. External heat increased the rate and extent of d-amphetamine absorption, with negligible differences in peak concentration and total exposure. d-Amphetamine PK were more protracted following d-ATS wear vs oral formulations, reflecting slower absorption with patch formulations.Short Description: d-ATS is the only transdermal system approved for ADHD patients ?6 years old. In this open-label study, d-amphetamine pharmacokinetics were evaluated following d-ATS application with/without external heat and compared among d-ATS, amphetamine-ER, and lisdexamfetamine. Heat application increased absorption rate and exposure during d-ATS wear, with negligible differences in peak plasma concentration and total exposure. d-Amphetamine exposure during d-ATS wear was lower for d-ATS vs amphetamine-ER and lisdexamfetamine, likely reflecting slower absorption with patch application.Name of Sponsoring Organization(s): Supported by Noven Pharmaceuticals, Inc.