Current Series: Managing OFF Episodes in Parkinson Disease

Daniel E. Kremens, MD, JD: What about a non-dopaminergic therapy for OFF time? Now we have istradefylline approved in the United States, which is a non-dopaminergic working on the A2A pathway, releasing that break on the indirect pathway. So that’s a way. It’s a once-a-day therapy. I think for many patients, that may be an option as well now.

Peter LeWitt, MD, M.Med.Sc: Looking at the clinical literature on that, patients who are often on multiple medications, taking istradefylline as a therapy, have enhanced their ON time, despite being on all of the other therapies in those studies versus placebo. And once-a-day therapy using sort of a standard dosing is appealing for the ease of therapy. We still await the roll out of this drug, so that all of us can start to get clinical experience. The last US studies were published in 2008, so this is a newcomer to the scene even though the medical literature goes back, at least in the US and European studies, more than a decade. The Japanese studies were complete in 2013. So it’s a new drug but with old….

Rajesh Pahwa, MD: But there are a lot of safety data also available because they have been around in Japan for a while. The other thing is, if you look at the data as far as the safety is concerned, it’s much better tolerated than some of the other drugs. And unlike MOA-B [monoamine oxidase-B] inhibitors, there are no drug interactions....

Peter LeWitt, MD, M.Med.Sc: And I think you can take away from the studies that the effect is fairly rapid in onset. It isn’t a 3-month trial to see if your patient is doing better. It’s also appealing to not even have to think of pharmacokinetics or other interactions. It’s sort of an all or none effect that istradefylline offers.

Stuart Isaacson, MD: It also offers this non-dopaminergic, no adverse effects of dopaminergic effects, so we tend not to see sleepiness. There seem to only be rare reports of compulsive behaviors. Orthostatic hypotension is not seen.

Peter LeWitt, MD, M.Med.Sc: Dyskinesias are about the only thing that might enhance. And of course, what do you do with dyskinesias? You lower the levodopa dose.

Stuart Isaacson, MD: Right. And then not only is istradefylline approved in this country as a non-dopaminergic therapy, but we also have amantadine, both immediate release and extended release, and then the bedtime high dose that’s been approved for dyskinesias, and it also helps OFF time. So glutamatergic mechanisms are also a rational way of thinking about….

Peter LeWitt, MD, M.Med.Sc: The fascinating thing, to me, is it improves OFF time in patients who are on all these other medications in the studies. So it’s a unique additive effect, or synergistic effect. So it isn’t 1 choice or the other. Going back to the notion of polypharmacy sort of makes sense if you read into the studies and look at what patients have been tested with. They’ve been on a lot of different drugs, but they do better. And then the question is, is it worth it in terms of cost, adverse effects, complexity?

Rajesh Pahwa, MD: To me, the interesting part with the amantadine ER [extended release] at bedtime studies was, like you said, not only did it reduce OFF time and dyskinesia, but it is the only medication we have that reduces OFF time and dyskinesias. The other interesting part is, when we looked at studies for which we started drugs for OFF time, patients have 6 hours of OFF time.

But when we look at a drug for dyskinesias, patients only had 3 hours of OFF time. And in spite of 3 hours, we were able to reduce it by 1 hour. Now whether that is because these patients were more optimally treated or whether the drug had unique non-dopaminergic effects, we don’t know. But it brings up an interesting point, that every patient out there doesn’t have 6 hours of OFF time when they get put in a clinical trial. I think those are the ones who are really undertreated. If we are treating them adequately and the dyskinesia is an issue, their OFF time is also less.

Stuart Isaacson, MD: We talk about patients who have dyskinesia, and we talk about patients who have OFF time. It’s the same patients. Our patients who have OFF time, at a certain dose of levodopa will invariably have dyskinesia often. And those with dyskinesia, at a lower dose will have OFF time.

Rajesh Pahwa, MD: That’s right.

Stuart Isaacson, MD: We’re focused so much on this balancing act and these non-dopaminergic therapies, and these infusion therapies give us another way of addressing the symptoms.

Daniel E. Kremens, MD, JD: I think another thing that many clinicians may not be aware of is, also, probably sometime in the next year or 2 in the US, we may have another COMT [catechol-o-methyl transferase] inhibitor as well as a once-a-day therapy that could also help us treat OFF time.