BACKGROUND AND OBJECTIVE: Rotigotine, a dopamine agonist, is used to treat Parkinson's disease and restless leg syndrome, with transdermal patches being the primary delivery method in clinical practice. However, quantitative information on the in vivo pharmacokinetics of rotigotine across various dosage regimens via transdermal administration remains limited, and this has been identified as a significant barrier to achieving precision medicine. This study aims to develop a novel physiologically-based systematic pharmacokinetic model tailored to rotigotine transdermal drug delivery. Based on the model, we quantitatively predicted rotigotine distribution patterns in target tissues to assess its in vivo efficacy and safety and to interpret the pharmacokinetic variability in transdermal patches according to covariate reflection. METHODS: The data used to develop the quantitative model included clinical outcomes from single (2-8 mg/24 h) and multiple doses (0.5-8 mg/24 h) of rotigotine transdermal patches administered to healthy adults and patients with idiopathic Parkinson's disease or restless legs syndrome. The model was designed to represent whole-body physiological systems, incorporate liver and kidney clearance mechanisms, and account for the specific physicochemical properties influencing drug permeation and distribution across various tissues. RESULTS: The model developed in this study effectively quantified the pharmacokinetic profiles of transdermal rotigotine within an acceptable variability. After transdermal application, rotigotine delivery to the target tissue, the brain, occurred rapidly, and the tissue concentrations at steady-state were approximately 10-fold higher than those in plasma. Incorporating weight as a covariate showed that in underweight individuals, tissue exposure to rotigotine increased by 1.61-fold, with a mean half-life extension of 1.50-fold compared to that of the normal weight population. CONCLUSION: The quantitative model proposed in this study serves as a foundational tool for advancing precision medicine, reliably characterizing the in vivo pharmacokinetics of rotigotine transdermal delivery across various doses and regimens.