Limits of Oral L-DOPA Delivery

As PD progresses, it becomes increasingly difficult to control the motor symptoms with drug therapy. The therapeutic goal is to achieve a near-constant level of dopamine in the brain, which requires achieving a near-constant level of L-DOPA in plasma. Low L-DOPA levels result in the return of motor symptoms, while high L-DOPA levels result in dyskinesias, hallucinations, and nausea. The motor symptoms and dyskinesias are collectively referred to as "motor complications." Standard L-DOPA treatment is oral delivery in pill form, which routinely results in over- and underdosing of L-DOPA.

Instead of a smooth, predictable therapeutic response to L-DOPA medication, people with advanced PD experience "motor fluctuations" such as failure of an L-DOPA dose to provide any therapeutic effect ("dose failure"), early loss of symptom control ("wearing off"), or sudden switches from "on" to "off" state. Advanced PD patients can experience many hours per day of motor complications.

Despite over 40 years of effort, drug makers have failed to develop a controlled-release oral form of L-DOPA that eliminates the extensive off time experienced by many people with advanced PD. This is due to the underlying causes of the response fluctuations: the short half-life of L-DOPA in the body and its absorption in only a short segment of the duodenum.

An improved approach to L-DOPA delivery is required to meet the needs of people with PD.