<p>Methylphenidate extended-release (ER) products are used in the treatment of attention-deficit/hyperactivity disorder (ADHD). These products exhibit diverse pharmacokinetic (PK) profiles that influence early systemic exposure and clinical response. To ensure bioequivalence (BE) for products such as Concerta and Ritalin LA, both the FDA and EMA recommend the use of pAUC_0-3h, with the EMA additionally suggesting the inclusion of C_max,0-3h. However, it remains unclear whether C_max,0-3h offers added discriminatory value beyond pAUC_0-3h in BE evaluation. The objective was to assess the sensitivity of early exposure metrics (pAUC_0-3h, C_max,0-3h, and C_3h) to changes in the SKAMP (Swanson, Kotkin, Agler, M-Flynn, and Pelham rating scale) response, a pharmacodynamic (PD) endpoint commonly used to assess clinical response in ADHD. PK/PD model simulations were performed for seven methylphenidate ER products. These products were categorized by PK absorption model: parallel dual first-order (e.g., Concerta) and parallel zero-order and first-order (e.g., Metadate CD). The PD model described placebo-adjusted SKAMP response based on simulated plasma concentrations. Simulations were conducted by varying the fast absorption rate constant (ka_Fast) to assess how changes in early exposure metrics affect AUEC_0-3h of the SKAMP response. The results indicated that pAUC_0-3h generally showed greater sensitivity to SKAMP response than C_max,0-3h and C_3h. Although C_max,0-3h exhibited high sensitivity in products with dual first-order absorption, its responsiveness remained inferior to pAUC_0-3h. These findings support the use of pAUC_0-3h as the primary early exposure metric for therapeutic equivalence assessment and suggest that C_max,0-3h may not provide further discriminatory value beyond that of pAUC_0-3h.</p> Graphical Abstract <p></p>