Effect of External Heat Application on the Pharmacokinetics (PK) of d-Amphetamine Transdermal System (d-ATS) and Comparison of PK of d-ATS With Oral Formulations
Background: d-ATS is a transdermal dextroamphetamine formulation approved for treating ADHD in patients ≥6 years old. This study evaluates the effect of external heat on rate and extent of dextroamphetamine (d-amphetamine) absorption following d-ATS application and compares d-amphetamine 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 7-day washout between periods. PK were compared using a linear mixed-effect model.
Results: With 9-hour 5mg d-ATS application, median Tₘₐₓ was 2h earlier and AUC₀₋₉ₕ 1.5-fold higher with heat than without. Geometric least-squares mean (GLSM) ratios (90% CI) for Cₘₐₓ and AUCо₋ɪɴғ with/without heat were 116% (109%, 124%) and 112% (104%, 120%), respectively.
With 20mg d-ATS application, GLSM ratios for AUC₀₋₉ₕ, Cₘₐₓ, and AUCо₋ɪɴғ were 48%, 33%, and 21% lower, respectively, for d-ATS versus lisdexamfetamine. d-Amphetamine exposures were comparable to those for amphetamine-ER, except for AUC₀₋₉ₕ (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 serum fluctuations. d-ATS provides d-amphetamine plasma concentrations for effective control of ADHD at lower total daily doses. External heat increased rate and extent of d-amphetamine absorption, with negligible differences in peak serum concentration and total exposure. d-Amphetamine PK were more protracted following d-ATS wear versus oral formulations, reflecting steadier absorption with patch formulations.
