A computational pharmacokinetic-pharmacodynamic framework for simulating and comparing individualized levodopa dosing...

Parkinson's disease is associated with substantial inter-patient variability in motor response to levodopa therapy, making long-term dose selection and scheduling challenging. Computational modeling provides a systematic approach for investigating how pharmacokinetic and pharmacodynamic variability may influence treatment outcomes. This study presents a computational pharmacokinetic-pharmacodynamic framework for simulating and comparing individualized levodopa dosing strategies in Parkinson's disease. The framework integrates multi-compartment drug disposition, effect-site dynamics, and a nonlinear exposure-response relationship, using parameter ranges derived from published clinical and modeling studies. A heterogeneous virtual cohort was generated to represent variability in absorption, clearance, distribution, and pharmacodynamic sensitivity, and simulation-based optimization was applied to evaluate the effects of dose size, dosing interval, and timing across representative patient scenarios. Simulations demonstrated how alternative dosing schedules influence effect-site exposure stability and predicted therapeutic response patterns under inter-patient variability. Sensitivity analysis further identified key parameters contributing most strongly to simulated exposure-response behavior. Rather than providing prescriptive clinical recommendations, the proposed framework serves as an in silico platform for comparing dosing regimens, evaluating scenario-specific strategies, and generating hypotheses for future data-driven validation. These findings highlight the potential of simulation-based PK-PD modeling to support individualized treatment exploration and future model-informed dosing research in Parkinson's disease.