Episode 6: New Levodopa Delivery Methods for Parkinson’s

Dan Keller 00:00 Welcome to this episode of Substantial Matters: Life and Science of Parkinson's. I'm your host, Dan Keller. At the Parkinson's Foundation, we want all people with Parkinson's and their families to get the care and support they need. Better care starts with better research and leads to better lives. In this podcast series, we highlight the fruits of that research — the treatments and techniques that can help you live a better life now, as well as research that can bring a better tomorrow.

More than 50 years after its discovery, levodopa is still the most effective treatment for Parkinson's, and many people can successfully manage their Parkinson's for years using oral dopaminergic medications. But after a while, some people experience frustrating off periods and dyskinesias, like we heard about in our previous episode with Dr. Irene Malaty. At the World Parkinson's Congress last fall, neurologist Mark Guttman, director of the Center for Movement Disorders in Toronto, Canada, told me about new levodopa delivery methods — some that are already available, and some still being studied — that may make it easier for people with Parkinson's to control their symptoms.

Dr. Mark Guttman 01:28 So I think the most important thing to emphasize to patients and their families is that levodopa is still the best drug that we have to treat Parkinson's. There are some issues with it, and there are some strategies to hopefully improve on the delivery. We know that people continue to have a response. One of the things from the lay literature gives patients — at least the ones I see — this false concept that levodopa only works for a certain number of years, five years, then it doesn't work anymore. That's just not valid.

The new delivery systems for levodopa include things that are just becoming available — the Duodopa infusions. This has been going on in Europe for the last 15 years, where patients would actually have an operation, a tube would be put into their small intestine, the duodenum, and there's a continuous infusion of levodopa within a solubilized gel that they would wear in almost a purse or a satchel with a pump. This can be very effective; however, it has risks and benefits. One of the risks is it costs about $70,000 a year, which is huge. You have to have an operation and be hospitalized. This has been acceptable in Europe, but I think we'll have major problems — at least in my country — having many people be able to get it.

Dan Keller 02:45 Even in Europe, it's been slow uptake, or limited uptake. So what kind of patients would this be most appropriate for?

Dr. Mark Guttman 02:51 This is for people with advanced Parkinson's who would not be deep brain stimulation surgery candidates, and who have significant response fluctuation. So that means they go from the medication working to not working at all, or having profound dyskinesias that are hard to treat when the medication is working.

So there are some new developments that hopefully will eliminate the need for surgery and hospitalization. One of the things that's coming along is with a company called NeuroDerm, where they've actually applied the same kind of strategy of infusing levodopa slowly in a constant mechanism, but in a patch formulation — there's a little needle that infuses it under the skin, and you wear a pump that's much smaller. So no operation — it can just be put on like a patch. That's coming along in development. They're looking at the equivalence to Duodopa as we speak, and because it's a generic drug, it doesn't have to go through all the stages of development. So I think they're hoping, within the next year or so, to have it available in Europe, and studies in North America are just starting.

Dan Keller 03:56 Would something like that still require some carbidopa orally, or given some other way?

Dr. Mark Guttman 04:00 Carbidopa is included in the formulation. There's another formulation that people talk about, which is sort of a gastro-retentive formulation. These are fancy capsules that have almost an accordion structure embedded into them. You swallow the capsule, it reaches the stomach, the capsule dissolves, this accordion structure opens up, and there's levodopa and carbidopa embedded into it that stays in the stomach for a long period of time and slowly releases levodopa.

So we don't know how effective that's going to be. We've heard in the lecture today that it's not just the absorption of levodopa from the stomach — there are other factors, including dietary things, that may affect the absorption of levodopa. So the subcutaneous administration may be better. But we've also heard that it depends on the dietary amino acids that people take, which may affect the transport from the blood to the brain. So in many respects, there are better delivery systems than we currently have. We know that levodopa in controlled-release Sinemet, for instance, doesn't work that well in this country. There are other options, including Rytary, which we don't have in Canada, so I don't really know how well that's working for people.

Dan Keller 05:19 Now, this retentive pill — it's been described as an accordion which is encapsulated and then kind of unfolds in the stomach. It sounds like it's more of a mechanical retention in the stomach. Do you end up with a bunch of these little things stuck in your stomach? What happens?

Dr. Mark Guttman 05:35 Well, it's interesting. When they approached us to do clinical trials, patients actually had to have endoscopies — gastroenterologists or surgeons looking into their stomach at the beginning and end of the study — just to see how these things work and whether they cause damage to the stomach. We don't know yet. When I talk to my colleagues that are involved in Duodopa centers, the gastroenterologists involved in placing the tube into the stomach say they actually see pills of levodopa that have been sitting there for days at a time, totally unabsorbed, just sitting in the stomach. So it'll be interesting to see what happens with these accordion devices. Hopefully they don't stick around and cause damage, but we don't know that yet.

Dan Keller 06:18 It sounds like some of these new things would have wide applicability. The Duodopa does not — that's an invasive procedure for later-stage patients. But some of these others — which ones would be for the general Parkinson's population?

Dr. Mark Guttman 06:35 I think all these advanced approaches to modifying levodopa delivery are really for the more moderate to advanced patients. Most of my patients in the early stages of Parkinson's are very well treated by the agents that we have. Levodopa/carbidopa — we have in Canada levodopa/benserazide — works very well, and I have patients that are still going strong 20 years later and don't need anything else. So it depends on the individual. I don't think these advanced delivery systems — unless they can show that continuous infusions prevent some of the problems we're seeing — are necessary for everyone. There's no evidence for that, at least in my mind at this time. So these are more meant for people who have developed wearing off or dyskinesias.

Dan Keller 07:19 There's also in development an inhaled levodopa — CVT-301, I think. Inhaled insulin sort of went nowhere. Do you think people are going to take to inhaled levodopa?

Dr. Mark Guttman 07:31 I'm not so sure. It depends on how they do with it, because you may get a big jolt and just be sent into wild dyskinesias, and may not be able to control motor functioning as well. We know that there were delivery systems that haven't been so effective — like apomorphine injections, for instance. There was sublingual apomorphine that was being developed, intranasal apomorphine that was going to be developed — they never went anywhere. So I think clinical trials are going to tell us how effective these things are.

Dan Keller 08:03 That may tell you safety and efficacy, but in the end, I guess it really depends on patient acceptance — and you'll probably only know that in a real-world situation, not a clinical trial.

Dr. Mark Guttman 08:14 Absolutely. If a patient is by himself without the injectable product on their body, it's not going to work because they won't be able to get to it. So if somebody can't use an inhaler properly because they're off, it may not work either. We learned a lot from when things are actually approved. In my career, we learned a lot about side effects of medications — for instance, all the impulse control disorders with the dopamine agonists that were not apparent during the clinical trial stage at all. So you're totally correct about that.

Dan Keller 08:49 Anything else in development that could potentially give better levodopa delivery?

Dr. Mark Guttman 08:56 What we heard from Dr. Nutt in the lecture today is that he was suggesting there may be some type of ester or formulation of levodopa that helps blood-brain barrier transport, or maybe even fusing it with other molecules that don't need the transport mechanism to get across. I hadn't been aware of that, and it would be interesting to see if there's some way of bypassing that amino acid transport mechanism to go from the blood to the brain.

Dan Keller 09:23 So that would probably depend on something that's lipophilic — fat soluble rather than water soluble.

Dr. Mark Guttman 09:29 Yeah, exactly. And how do you get rid of that part of the molecule before it gets to the nerve cells? He also mentioned something that I was aware of, but I'm not sure how easy it's going to be — which was using adenoviral vectors to deliver aromatic amino acid decarboxylase to the brain. So giving the metabolic machinery in brain cells or glial cells the ability to take the levodopa and convert it into dopamine where it's needed. This would be very invasive — a stereotactic injection, meaning making a hole in the skull, putting a probe into the brain, and inserting either viruses that deliver this enzyme or some other mechanism to produce dopamine in the brain. That would be really interesting, but what are the risks? We don't really know at this time.

Dan Keller 10:29 In our conversation, Dr. Guttman mentioned a lot of potential treatments with new and complex modes of action. For more information, visit parkinson.org/podcast and click on the link for this episode, or call our helpline at 1-800-4PD-INFO.

If you want to leave feedback or comments on this podcast or any other subject, you can do so at parkinson.org/feedback. We'll respond to some questions in future episodes. At the Parkinson's Foundation, our mission is to help every person diagnosed with Parkinson's live the best possible life today. To that end, we'll be bringing you a new episode in this podcast series twice a month.

Until then, for more information and resources, visit parkinson.org or call our toll-free helpline at 1-800-4PD-INFO — that's 1-800-473-4636.

A resource you may find particularly helpful after today's conversation with Dr. Guttman is our free book, Parkinson's Disease Medications, which goes into detail on medications for all aspects of Parkinson's, including motor symptoms and non-motor symptoms such as mood and sleep disorders, gastrointestinal issues, and more.

Thank you for listening.

Host Dan Keller and Dr. Guttman discuss several levodopa delivery methods that are designed to help reduce “off” time. Everyone’s Parkinson’s journey is unique, so whether these methods are right for you will be a decision for you and your health care team. There is a PD myth that levodopa works for a few years and then stops. This is not true; you just need to work with your doctor to find the right frequency, dosing, and delivery methods. In general, the delivery methods Dr. Guttman describes are for people who have had Parkinson’s for years and experience “on-off” fluctuations.

Here is some more information on many of the topics Dr. Guttman brings up:

• A continuous gel infusion of levodopa is available in the U.S. as Duopa (it is called Duodopa in other countries). Visit our Duopa page for more information. Carbidopa is included in the formulation to prevent the nausea that can be caused by levodopa alone.
• What you eat and when can affect the absorption of levodopa. Listen to our nutrition podcast with Dr. Bas Bloem for more information.
• Rytary is carbidopa-levodopa that has both immediate-release and extended-release forms in one pill and is supposed to reduce “off” time. It is not interchangeable with dosages of other carbidopa-levodopa products, so share this Rytary dosing guide with your provider.
• This interview was recorded at the World Parkinson Congress. Dr. Guttman mentions a presentation by Dr. Jay Nutt: Levodopa Over the Last 50 Years: Where We’ve Come and Where We Are Going? (Free registration to watch.)

Dr. Guttman is a movement disorder neurologist at the Centre for Movement Disorders in Toronto, Canada. He provides specialized neurological services to people with movement disorders and is involved with clinical research at the Centre and at the University of Toronto.