There is no cure or disease-modifying treatment currently available for Parkinson’s disease (PD). Current treatment strategies are focused on the management and reduction of the major symptoms of the disease and related disabilities, with treatment becoming less effective over time as the disease progresses. The standard of care regimen for the symptomatic treatment of PD is levodopa, which was the first drug approved specifically for PD nearly 50 years ago. Levodopa is mostly administered orally in combination with a peripheral dopamine decarboxylase inhibitor, usually carbidopa, in order to increase the amount of levodopa that enters the brain, and to decrease the frequency of dopamine-related side effects (namely, nausea, dizziness, and orthostatic hypotension). Levodopa improves motor function as long as it produces dopamine levels in the brain that remain within an individual’s therapeutic range. Carbidopa/levodopa is initially given three times a day, but its frequency of administration increases as the disease progresses. Carbidopa/levodopa must be started at the lowest dose and titrated slowly with changes on a weekly basis in order to lessen the occurrence of dopamine-related adverse events (AE’s).1
Levodopa, however, has several limitations relating to its half-life, oral delivery and the motor dysfunction in PD patients:
- Levodopa has a short half-life, which decreases as the disease progresses, resulting in the need for higher and more frequent dosing;
- Levodopa must be actively absorbed, or transported, through the gastrointestinal tract into the bloodstream. The ability of levodopa to reach its specific absorption site is dependent on its ability to move reliably through the gastrointestinal tract. PD patients have slowed gastric motility and erratic emptying resulting in fluctuating and unpredictable levels of levodopa in the bloodstream; and
- Gastrointestinal transport is also frequently slowed by meals, decreasing the amount of levodopa that can be absorbed when it is given orally near mealtime. Additionally, in the specific portion of the gastrointestinal tract where this transport occurs, levodopa competes with food (specifically amino acids in food) for active transport.
As a result of these challenges, patients are unable to predictably and reliably count on existing medications or therapies to keep themselves in their therapeutic range and to treat their PD symptoms. Despite efforts by physicians to continually optimize and individualize patients’ regimens, the unreliability of oral levodopa results in episodes of unexpected and often rapid return of PD symptoms. The re-emergence of PD symptoms is referred to as an OFF episode. OFF episodes are thought to occur when brain dopamine levels fall below a critical threshold to sustain relatively normal motor function, or ON. It can be a period of time when a patient’s PD medication is not working adequately to alleviate the patient’s PD symptoms, when the medication has a delayed effect, or does not work at all. On the other hand, excessive levels of dopamine in the brain can cause dyskinesias, or extra, involuntary movements. As the graphic below depicts, as the disease progresses, a PD patient’s therapeutic window narrows and levodopa becomes less effective resulting in increased severity and duration of OFF episodes and ON time with dyskinesia.
1) WEBMD: DRUGS & MEDICATIONS (Carbidopa-Levodopa) Retrieved from http://www.webmd.com/drugs/2/drug-3394-41/carbidopa-levodopa-oral/carbidopa-levodopa-oral/details