Levodopa is the current standard of care for Parkinson's disease, but chronic therapy has been associated with motor complications. Maintaining sustained and constant blood concentrations may reduce these complications, but designing a controlled release formulation (CRF) that delivers such a profile is challenging. To facilitate the development of such formulation, we developed and validated a physiologically based mathematical model. Analysis of experimental results using the model shows that levodopa is well absorbed along the entire small intestine and that levodopa in the stomach causes fluctuations during the first 3 hours after administration. Based on these insights, we used the model to develop guidelines for an optimal CRF for different stages of PD. Such formulation is expected to produce steady concentrations and prolong therapeutic duration by 50% over a common CRF with a lower dose, thereby increasing the patient's compliance with the dosage regime.