What to Know About Infusion Therapies in Parkinson's Disease

Medscape

5 days ago

This transcript has been edited for clarity.
Indu Subramanian, MD: Hi, everyone. This is Dr Indu Subramanian, from UCLA. I'm excited to have you join us at Medscape today. I'm delighted to have my friend and close collaborator, Professor Ray Chaudhuri, join us from Europe.
He's a professor of neurology at King's College London and King's College Dubai. He's a groundbreaking clinician who's really changed the field of movement disorders and Parkinson's. He's introduced us to many novel therapies over the years and set the stage for nonmotor Parkinson's disease.
It's been a pleasure to learn from him over the years. I'm excited to have him teach us about the many options in the infusion therapy world.
Welcome, Ray.
K. Ray Chaudhuri, MD, DSc: Hi, Indu. Thank you for having me.
Infusion Therapies
Subramanian: One of the things that we wanted to talk about today was infusion therapies, including subcutaneous foslevodopa/foscarbidopa. There's also been, as you know, a longstanding history that you've had exposure to of apomorphine pumps, Duopa pumps, and the patch.
Chaudhuri: Infusion therapies have been a mainstay, shall we say, underpinned advanced therapies for Parkinson's for a long time. In fact, originally it was developed in the 1970s, but commercially, I think the first sighting of infusion therapy in Parkinson's, certainly in Europe and in the UK, came in the 90s with apomorphine: apomorphine infusion and injection. I understand apomorphine injection is available, and apomorphine infusion has recently been made available in the US. The subcutaneous field developed into infusion of levodopa, and there are two forms.
The first one, commercially available now in many countries in the world, is the foslevodopa/foscarbidopa preparation, which is an approved drug of levodopa and carbidopa. When infused with this very small Vyafuser pump, it immediately gets converted to levodopa and carbidopa in the skin and is then absorbed and provides continuous nerve stimulations over 24 hours.
Another form, is the NeuroDerm product, which is levodopa infusion with carbidopa, not foslevodopa/foscarbidopa. That's infused with a different pump system with two syringes, but that's not yet commercially available.
The one that's commercially available is foslevodopa/foscarbidopa, and there is an accumulated experience of over 67,000 patients in the world now with the use of this product. It is novel in the sense that it's the first time ever levodopa has been made available to be given in a subcutaneous infusion format.
It was previously available as intrajejunal levodopa with levodopa/carbidopa, Duodopa or Duopa. Now, it's available subcutaneously, and the great advantage is that it's much less invasive. It doesn't require a surgery, which you needed with the Duodopa. Third, it is probably the only treatment option at the moment that really effectively gives you a 24-h treatment option, so it gives you treatment option during the day and through the night.
The other additional advantage of this very sophisticated pump is that it allows you to do the setting high and low. For instance, you can set the dosing at a high level during the day, depending on the patient's requirements, and then cut the dose down at night about 30%, which is your normal dopaminergic neurotransmission as it occurs during the sleep-wake cycle.
It has great advantages also over the early morning OFF periods, which many other therapies do not really affect, because they're usually effective for only 14 hours. You don't get that cover all through the early morning periods when the patients are often OFF. They wake up with severe, dystonic pain, difficulty turning in bed or passing urine, urgency, and even depression or other nonmotor fluctuations that might occur. All of that seems to be helped by the use of foslevodopa/foscarbidopa.
Infusion vs DBS
Subramanian: Sleep is so important in our patients. I think we've really under-recognized that. You've been doing a large amount of work and even put a whole collection of articles together on sleep. It's just pretty amazing how little we have to offer patients in the sleep realm, and it can affect, presumably, cognition, daytime symptoms of motor and nonmotor issues, and quality of life both for the patient and their caregivers who are also not getting sleep.
In the landscape currently of infusion therapy and deep brain stimulation (DBS), you have DBS available in the UK as well as other parts of Europe, along with these infusion therapies. You've had these infusion therapies for much longer than we've had in the United States, for example. Can you tell me a little bit about the decision algorithm if you have a patient in front of you, what type of patients do you send to DBS?
Chaudhuri: Great question. Before I go into the DBS option, I think you mentioned a really important part, which is sleep. I think sleep is often under-recognized. It's part of this dashboard of Parkinson's, which we introduced, and we should be recommending at least 6-8 h of sleep per day because of the activation of the glymphatic system and potential effect on amyloid clearance.
Any treatment option like foslevodopa/foscarbidopa, which is helping this early morning OFF period — and we've shown that in two long-term studies— actually helps with sleep, because it cuts down the fragmentation of sleep in early morning and, therefore, helps you have a good quality of sleep, which will then indirectly affect the issues around cognition and so on. That sort of study will need to be done in the future, but it's an enormously new development and a great advantage of this 24-h therapy.
In relation to an algorithm, in addition to DBS and apomorphine, now we have foslevodopa/foscarbidopa, levodopa infusion into the jejunum with Duopa, but also LECIG gel, which is levodopa/carbidopa/entacapone infusion. That's also available in some countries in Europe.
In terms of when, ideally, you would choose DBS, my algorithm would suggest the age parameter. Most centers would operate up to 70 years of age. After 70, it becomes a little bit tricky. It depends on the local surgeon's preference and the patient's condition. If you look at people below age 70, if they have clear dyskinesia as the dominant problem or pharmacoresistant tremors, in that situation, I would go with DBS first. That seems to be very effective and a quick fix.
Now, the data would also suggest patients must be given an option of subcutaneous therapy. Some patients might want to try the subcutaneous option first, which also works for dyskinesia, and specifically works very well for early morning OFF and sleep. They may say: What if I try that first, and if that doesn't work, I can still have DBS?
Over the age of 70, at this moment in time, foslevodopa/foscarbidopa infusion would probably be the first choice, given that apomorphine has dopamine agonist side effect issues, such as somnolence, postural hypertension, and the potential for impulse control disorder.
I would think most people would go with the levodopa-based option, but there are, of course, situations where you might want to use apomorphine. If somebody's very profoundly depressed or is very anhedonic or apathetic, you might want to try apomorphine first because of it's antagonist effect, which helps with apathy and depression.
Below the age of 70, if a patient has dominant problems with bad dyskinesia, troublesome dyskinesia, diphasic dyskinesia, ballistic dyskinesia, along with pharmacoresistant tremor, probably DBS is the first option. Such a patient should also be given the option of subcutaneous therapy, and they might actually choose subcutaneous levodopa or foslevodopa/foscarbidopa first because it also has antidyskinetic action after an initial period when the dyskinesias might be there.
After a few weeks, there's a delayed effect, the dyskinesias tend to go down. If that doesn't work or if the patient develops skin issues or neuropsychiatric problems, DBS can still be an option. Over the age of 70, however, we would probably go for a subcutaneous option first. The majority of patients will probably choose levodopa, but apomorphine remains a potential option if the patient's severely depressed or apathetic. You want to give apomorphine and agonist properties a little try first.
Skin Side Effects
Subramanian: You mentioned skin issues. Could you describe those a little bit?
Chaudhuri: With any subcutaneous anti-parkinsonian treatment, skin problems become an issue with chronic therapy. It was an issue with apomorphine. Apomorphine causes nodules and you have to be aware of that and take action so that you don't get these nodules or reduce the frequency.
With foslevodopa/foscarbidopa, the situation is a little bit different because of the pH issue and possibly because there's some skin intolerance with levodopa. We had recently suggested that there are asymptomatic skin problems and symptomatic skin problems. Among the symptomatic skin problems, you can get redness or a little bit of inflammation around the area.
Very rarely, that might develop into cellulitis. That's what we must prevent. You can take preventive actions. For instance, you can use a low pH soap water wash. You can change the needles daily. You can keep the skin area very clean. At the first sign of any inflammation or infection, use a combination of antibiotics and perhaps some steroids as well.
These are potential steps you can take, but that's something to remember. I think with good management, it should not be a major issue.
The other side effect problem that you might get is neuropsychiatric problems. We have noticed this, and it might be related to the overnight infusion. What one might have to do is cut down the dose of the overnight infusion — and in very selected, rare cases — even stop the nighttime infusions for a few days and then restart it. That tends to sort the problem out. In some cases, you might need to use a drug such as quetiapine. When you're selecting a patient, therefore, it's important to screen for this or keep in mind the use of nighttime infusion and the prospect of any psychosis issues.
Subramanian: That makes sense. Preventing hallucinations by not infusing as much medicine or no medicine overnight could be an option. This type of therapy gives you some flexibility there, which sounds great.
I think this has been really edifying to me. I love learning from you. Thank you so much for joining us in your busy day there. We appreciate viewers out there on Medscape joining us as well.