Pharmacokinetics at Different Application Sites and Dermal Safety Analysis of Dextroamphetamine Transdermal System...

Dextroamphetamine transdermal system (d-ATS) is the first and only amphetamine-based transdermal system FDA-approved for attention-deficit/hyperactivity disorder (ADHD) in adults and children aged ≥ 6 years, providing an alternative to oral stimulants. Although transdermal systems can cause local skin reactions, in the d-ATS pivotal study, no discontinuations due to patch application site reactions occurred, and discomfort/pain typically resolved within 2-4 h post-application. d-ATS is approved for five bilateral application sites (10 unique locations). This paper evaluates the pharmacokinetic (PK) bioequivalence between different application sites and summarizes dermal safety and irritation findings from four d-ATS clinical studies (studies 1-4).

The application site PK bioequivalence study was a single-dose, open-label, 5-way crossover study assessing amphetamine bioavailability, discomfort, and irritation in healthy adults after a 9 h application of 20 mg/19.05 cm² d-ATS to five distinct sites. Other studies, studies 1-4, conducted in healthy adults or patients with ADHD, evaluated dermal irritation from d-ATS alone or vs placebo under intended-use or exaggerated-use conditions.

The application site PK study population included 50 patients. All 90% CIs for key exposure parameters fell within the FDA-specified bioequivalence limit of 80-125%, demonstrating bioequivalence across five application sites, with no discontinuations related to irritation or discomfort. Under intended-use conditions (site rotation consistent with approved d-ATS use; studies 1 and 2), instances of skin irritation were not clinically meaningful (≥ 3 point Bowman and Berger scale combination score). Under exaggerated-use conditions consistent with FDA guidance (studies 3 and 4), clinically meaningful irritation occurred in 55-61% of patients; 3/249 discontinued because of d-ATS-associated skin irritation, which generally resolved within 15-27 h after patch removal.

d-ATS's benefits as an additional treatment option for ADHD in children, adolescents, and adults likely outweigh any minor irritation concerns. Transdermal delivery confers practical advantages, and the range of bioequivalent application sites can help minimize dermal irritation. d-ATS's efficacy has been established in prior clinical studies and published elsewhere. Overall, d-ATS represents a valuable, flexible treatment option for children and adolescents with ADHD.