The expert panel discusses advances in formulations of carbidopa/levodopa and identification of OFF and ON time in patients with Parkinson disease.
Daniel E. Kremens, MD, JD: One thing I think is interesting is among the different formulations of carbidopa/levodopa, Bill, you mentioned there are some extended-release formulations. There seems to be some confusion among patients and practitioners about some of the longer-acting formulations of carbidopa/levodopa. There’s carbidopa/levodopa controlled release [CR], which is basically carbidopa/levodopa put into a wax matrix, and then this releases irregularly and slowly. It lasts a little longer than instant-release levodopa, but it’s a technology that’s been around since the 1990s. More recently we saw the introduction of carbidopa/levodopa extended release [ER], and this is a different drug than controlled release. This is a drug, it’s a capsule where one-third of the beads are an instant-release preparation, and the other two-thirds are a proprietary extended-release formulation. So, these longer-acting forms of levodopa themselves are very different drugs.
Rajesh Pahwa, MD: In the CR preparation, it has a slow rise in level, so it often takes much longer for it to kick in, and that’s a big disadvantage of the CR. The levodopa ER capsules are helpful in certain patients, but in some patients it can be challenging to switch them from immediate-release to extended-release capsules.
Robert A. Hauser, MD, MBA: If I could just interject, one thing we’ve seen in our clinic is that often carbidopa/levodopa CR is mislabeled on the bottles as carbidopa/levodopa ER, or extended release, and that creates a lot of confusion. We’ve talked about the difference, but this labeling adds to confusion, so patients and clinicians need to be aware of that.
Daniel E. Kremens, MD, JD: That’s a really interesting observation, because earlier this week, a patient brought in their levodopa and showed me the bottle, and I had prescribed CR, and the bottle contained CR, but it was labeled ER. It made the discussion very confusing. The patient didn’t understand initially what I was saying when I was explaining the differences in the medications. Fernando, how have you adopted Parkinson disease treatment advances and these different formulations to try to improve patient care in your practice?
Fernando Pagan, MD: I think the discussion Dr Ondo gave us about all the different medications we have is exciting with what’s happened in Parkinson disease because when we just had levodopa, we had to be creative. We had the immediate-release carbidopa/levodopa or the CR, and this was in the ’80s and ’90s; that’s basically the only type of levodopa formulations we had. We had to get creative, and I remember doctors using liquid levodopa, or giving half a tablet every 90 minutes or every 2 hours, or a full tablet every 2 hours for some of our patients with advanced Parkinson disease having significant motor fluctuations. Having these extended formulations and adjunctive therapies have been helpful in understanding how to use them. When we take a look at some of the studies that have been done like ADVANCE-PD and ASCEND-PD, we can see that using these extended-release formulations of carbidopa/levodopa reduce OFF time and improve ON time without troublesome dyskinesia. That’s one of the first things I usually do, I go to the extended-release formulations first and try to see if I can decrease those motor fluctuations for our patients. Then I take advantage of the fact that we have adjunctive medications like MAO-B inhibitors, dopamine agonists, COMT inhibitors, and A2A antagonists that can help reduce that OFF time.
It becomes challenging though as the disease progresses for some patients. This is where you may think of more advanced therapies like deep brain stimulation that can reduce the OFF time or the time of dyskinesia, but also reduce the overall need for levodopa medication. You could also think about more continuous delivery of carbidopa/levodopa. This is where carbidopa/levodopa enteral suspension could be beneficial for advanced patients. And hopefully soon we are going to have more subcutaneous infusions available, whether with a dopamine agonist like apomorphine or phosphorylated carbidopa/levodopa formulation, or other formulations of carbidopa/levodopa. It is exciting to be able to hopefully enhance or improve the way we deliver carbidopa/levodopa and use some of these technologies soon. They have already been used in the diabetic world, using subcutaneous infusions for insulin. Hopefully, we can translate that here in Parkinson disease and reduce OFF time and improve ON time without troublesome dyskinesia in our patients.
Daniel E. Kremens, MD, JD: Bob, Fernando was talking about reducing OFF time, and I guess just for definition, OFF time is when medicines fail to give the expected benefit, or you see a return of symptoms before the next dose of medication. Do you think that’s a fair way to describe OFF?
Robert A. Hauser, MD, MBA: Yeah, I think so. I say ON is when medication is providing good benefit for mobility, slow and small movement, stiffness, and in some patients, tremor. Tremor is difficult to throw in here because it sometimes responds and sometimes doesn’t. Tremor increases or decreases based on emotional activation, so I tend not to throw tremor into that definition. OFF is when medication has either worn off or not yet kicked in. In the clinic I like to ask patients, “Does your medication last from dose to dose? Is it providing a benefit? Does it last from dose to dose? If not, how long is it wearing off before the next medication kicks in? What happens in the morning when you first wake up? Is that your best time, or do you notice that the medications from the day before have worn off? And if so, how long does it take for that first dose of the day to kick in?” I also ask the care provider, the spouse or whoever’s with the patient, “Can you tell when the medication’s working? Do you see a difference?” It’s important to ask the question, what do you see that’s different? It’s important to think about the motor features because there are many things that vary through the day that may not be part of the dopaminergic response. Patients get tired in the afternoon, they may experience episodes of hypotension, etc. Those are the things that can get a little confusing.
Transcript Edited for Clarity