Daniel E. Kremens, MD, JD, reviews the underlying pathophysiological factors that contribute to OFF episodes.
Daniel E. Kremens, MD, JD: What’s the underlying pathophysiology of OFF? We think there are central and peripheral mechanisms of OFF. Centrally, Parkinson disease is a progressive disease. As the disease progresses, the patient has a loss of presynaptic dopaminergic neurons that allow the patient to metabolize and store and release dopamine. Early on in the disease, the patient has enough presynaptic dopamine neurons so that they can store the extra dopamine that they’re getting from their exogenous levodopa and release it over the course of the day. The patient may need their levodopa only 3 times a day, and that can cover them because they have buffering capacity from the ability to store and release the extra dopamine. But as disease progresses, they lose that capacity because they have fewer presynaptic neurons. This leads to what we classically call wearing off. The medicine may have lasted initially 5 or 6 hours for each dose, but now it starts to last 4 hours, then 3 hours. We need to increase the dosing of the levodopa from 3 times a day to 4 or 5 times a day, for example.
In addition to the central mechanism of OFF, there are also peripheral mechanisms involving a dysfunctional GI [gastrointestinal] system. This is common in Parkinson disease. First, the levodopa has to get down into the intestine, and that involves using a dysfunctional swallowing for many patients. For a dysfunctional stomach, the levodopa may sit in the stomach due to gastroparesis and simply not move forward into the intestine. Once in the small intestine, there can be issues with transport and getting the levodopa from the gut into the bloodstream through the large neutral amino acid transporters. This competes with dietary protein. This can be a problem for some patients. In addition, there may be small intestinal bacterial overgrowth, H pylori [Heliobacter pylori] infections, or bacteria in the microbiome that can interfere with levodopa. All these things can have an impact. Finally, there’s extensive metabolism of levodopa in periphery, including by dopamine decarboxylase and catechol-O-methyltransferase, or COMT. Only about 1% of levodopa that a patient takes makes it to the brain due to this extensive peripheral metabolism. With the addition of a dopamine decarboxylase inhibitor, the number increases to about 10%. But given both the extensive peripheral metabolism, the gut dysfunction, and the central mechanisms, all of these contribute to OFF inpatients.
Transcript edited for clarity.