Comparing daytime pharmacokinetic and pharmacodynamic profiles of once-daily lisdexamfetamine versus twice-daily dexamfetamine in adult ADHD.

Dexamfetamine (DEX) and lisdexamfetamine (LDX) are both prescribed to treat adult ADHD in the Netherlands. LDX is marketed as a long-acting prodrug of DEX requiring once-daily dosing, unlike DEX, which typically is administered two times daily. However, empirical evidence for this distinct dosing regimens remains sparse. This open-label, cross-over study compared the daytime effects of bioequivalent doses of DEX (twice daily) and LDX (once daily) in sixteen adults with ADHD. It was hypothesized that twice-daily DEX is associated with a faster onset and longer duration of clinical effect due to the second dose, compared to once-daily LDX. Dexamfetamine plasma concentrations, ADHD symptoms, subjective effects, and vital signs were assessed at multiple time points over 12 h post-dose. A significant treatment-by-time interaction was observed for plasma concentrations (F(5,165) = 12.21, p < 0.001), as well as for subjective effects related to wanting more drug (F(4,135) = 2.47, p = 0.047), and contentedness (F(4,135) = 2.50, p = 0.045). We further report a slope-dependent relationship between plasma levels and treatment effects, subjective effects fluctuations appeared more pronounced with DEX, potentially increasing the perceived need for repeated dosing and titration complexity. In contrast, the smoother pharmacokinetic profile of LDX provides objective support for current clinical guidelines that often prefer long-acting formulations for adult ADHD due to their potential for improved adherence and reduced burden of titration.