Optimal Management of OFF Episodes in Parkinson's Disease - Episode 2

Apomorphine Subcutaneous Injection: Historical Perspective for Off-Episodes in Parkinson’s Disease

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Daniel E. Kremens, MD, JD: We’ve had a lot of recent approvals and some data. Let’s look at some treatment options, starting with some dopamine agonist options. Let’s discuss how you think about the following dopamine agonists that have been approved or are in development to treat off-episodes. Let’s talk about 3 different apomorphine products, their method of action, and delivery system advantages.

First, a lot of people don’t realize when they hear the term apomorphine that it has nothing to do with morphine. Apomorphine means “away from morphine.” Even the word doesn’t mean morphine, although that term is in it. I know people see that and say, “Why would you give morphine to a Parkinson patient?” It has nothing to do with that. I always like to clear that up right up front.

The other thing is apomorphine is 1 of the oldest treatments for Parkinson disease [PD], historically. It was approved for treatment in the 1990s in a subcutaneous form in Europe, but it’s been around as a treatment for a long time prior to that. Let’s talk a little about apomorphine hydrochloride subcutaneous injection, commercially known as Apokyn. Why don’t you tell me a little about your experience with Apokyn [apomorphine hydrochloride] dosing, efficacy, safety, and administration.

Rajeev Kumar, MD: I started using Apokyn [apomorphine hydrochloride] when I was a fellow in the early 1990s. We used it extensively just prior to the beginning of device-aided therapy with deep-brain stimulation. We had lots of patients who had severe unpredictable off-episodes. They had PD for 10, 15, 20, or more years. We could not administer levodopa frequently enough or productively enough, and using Apokyn [apomorphine hydrochloride] was a tremendous advantage. We used it because it kicks in very quickly, as we’ll talk about in just a moment, and very predictably. 

We actually used it when we started doing stereotactic neurosurgical procedures. We’d administer it intraoperatively while recording individual cells in the pallidum and subsequently in the subthalamic nucleus to look at how we could alter firing rates and patterns. There are several publications that came out of that experiment. We’d see them preoperatively, we’d find out the right dose that kicked them in when they were off medication overnight—as you typically have them intraoperatively—we’d get very nice recordings, and then we’d inject them, taking them from a fully off to a fully on state right there in the OR [operating room] with electrodes in their brain. The effect is outstanding. You can hear the patient’s tremor cells firing away and then inject them. Ten minutes later the patient’s tremor is gone and the tremor cells are no longer firing.

Daniel E. Kremens, MD, JD: Even though levodopa is thought of as the gold standard for Parkinson disease, apomorphine is the only drug that has that levodopa-like response. In fact, as we’ll discuss, it’s potent, fast, and reliable.

Rajeev Kumar, MD: Absolutely. Like levodopa, it’s a nonselective D1 and D2 agonist. Most dopamine agonists that we administer orally are predominantly D2 preferring—D2, D3, D4, especially D3—when we think about pramipexole, ropinirole, and rotigotine. This [apomorphine hydrochloride] truly can create a full on response. Administering these other orally administered dopamine agonists typically can get somebody partly on, but in advanced disease, these by themselves cannot achieve the full levodopa-like effect. Take somebody, for example, having withheld medication overnight, to treat that early morning off-episode they can inject themselves and can jump-start, as they might call that. The patient is off, very immobile, and in bed, and they cannot get up and walk. They can inject themselves with Apokyn [apomorphine hydrochloride]. Typically the onset is very quick, 10 or 15 minutes, but the offset is also very quick. The typical duration of action of Apokyn [apomorphine hydrochloride] is about an hour. It gets you on but it doesn’t keep you on unless you have something else that will do so.

The patient who has early morning akinesia and does not have an opportunity, for example, to take oral levodopa during the night because they’re sleeping well—let’s say they’re sleeping 7 or 8 hours—is now having an off-episode. They’re sitting in bed and they’ve got to get going. They’ve got to get to work. They can inject themselves with Apokyn [apomorphine hydrochloride] and simultaneously or shortly thereafter take oral levodopa. Apokyn [apomorphine hydrochloride] kicks in within 15 minutes or so. They’re up and in the shower in 30 minutes. While they’re in the shower, the levodopa kicks in. By the time the Apokyn [apomorphine hydrochloride] starts to wane in effect, levodopa is fully on. They’re doing well right through breakfast and can get on with their day and get to work or wherever they need to be. That’s a great therapy for patients who have early morning akinesia.

Another strategy is if a patient gets up during the night, for example—many patients get up to urinate 2 or 3 times a night—they can take levodopa during the night. Taking a delayed-release formulation or controlled release—eg, Sinemet CR [carbidopa-levodopa CR]—can be a helpful strategy because you’re not trying to get the patient fully on at that time. What you’re trying to do is get the patient on, at least partially on, or have a good plasma level of levodopa so that when they wake up they’re not so immobile. They’re at least half on, if not fully on, and can take their next dose of levodopa and predictably get on quickly rather than having a delayed on response or perhaps a dose failure. 

That’s another strategy that can be used because Apokyn [apomorphine hydrochloride], although a good medication, it is not ideal for all patients. Especially if you have a very immobile patient in the morning who maybe can’t self-inject and doesn’t have a caregiver available. But a majority of patients can give Apokyn [apomorphine hydrochloride] themselves, especially using the penject system. It’s very simple, and it’s very well tolerated.