Sunovion Expects APL-130277 Will Ably Treat Off Episodes, Awaits FDA Decision

Potential Parkinson's Treatment for Off Periods Shows 'Key Benefit' of Working Well, Sunovion Says

APL-130277 (Sunovion) is a sublingual version of apomorphine, a dopamine agonist. As such, it offers a more convenient delivery than present versions of apomorphine, which need to be injected (e.g. Apokyn).

Its purpose is supposed to be dealing with "off" periods. It is suitable for this because it reaches maximum concentration in about 20 minutes, as compared to the 60 minutes of levodopa/carbidopa.

Apomorphine's weakness is that it has a short half-life, 30 minutes as compared to the 90 minutes of L/C. So unless you take other medication you will go "off" quickly.

I think most people will benefit more by having their present drug regimen optimised; making use of the longer half-life of other drugs to give a smoother control of the symptoms.

There is a role for this drug in the case of unexpected "offs", but one has to be careful. Suppose you take a dose of L/C, which has its impact delayed by something in the diet. You go "off" and take the apomorphine, just before the L/C dose kicks in.

John

i have a different opinion, i think there is a need for a "rescue" drug to get you back on in 20minutes or so. there are some people that can't tolerate longer lasting agonists and can't afford rytary so have to struggle with C/L and C/L extenders like entacapone and have to deal with the results of eating too much protein if they loose their self control and overindulge in protein. if i do that, i have to wait up to 2hrs before taking C/L. i will take an extra 100mg if C/L when i know i've eaten too much protein but i risk having my BP going too low. if this form of apomorphine lets you splurge on protein once in awhile - assuming it isn't greatly affected by protein - then for me it fills a valuable need. i recently added MIRAPEX, didn't like it but toughed it out to reach 3mg/day and had to stop, started seeing / hearing things that weren't there. couldn't tolerate amantadine, entacapone added maybe 45minutes at the best, i have high blood pressure so can't take a mao-b inhibitor so not that easy to adjust my drug regime, especially since i am taking enough C/L that i risk my BP going too low. so a convienent quick acting apomorphine would be a godsend for me if it significantly reduces the inevitable OFF time if i happen to eat more than 4 grams of protein which i do once a day.

I have the same issue witha 2-3 hour wait after eating protein and sometimes that dose never kicks in, rare but it happens. This article says one layer contains an acid neutralizer "thought to improve absorption," that doesn't seem like a guarantee to me. When I started reading this article, I thought I was reading about the inhaled version of the rescue drug which I have been excited about. That one I feel sure would bypass the digestive process. My neuro told me a while back that he thought 5-10 minutes for the inhaled version to take effect. This is the last I have seen about Acorda and its inhaled version:Inhaled Levodopa for 'Off' Time Moves to FDA Review. UPDATE September 13, 2018: Acorda Therapeutics, Inc today announced that the U.S. Food and Drug Administration (FDA) has extended its decision date on inhaled levodopa to January 5, 2019 (Feb 20 2018).

i worry about inhaled drugs in general, especially a powder. but i think the expected high price for inhaled C/L will limit it to emergencies so noone is going to replace oral C/L with inhaled. it's too bad it's taking so long to bring it to market. keep in mind that the sublingual apomorphine also goes directly into your blood and sounds like it gets there quicker than inhaled C/L and in a much easier to use and likely safer mode of delivery for those with respiratory difficulties. can't really compare apples to apples with these 2 drugs and there is the issue of how tolerable is low dose apomorphine, you can't really know until it gets out into the general public imho, injectable or continuous delivery apomorphine takes some getting used to under a dr's supervision.

In order to better understand the effect of apomorphine used as a rescue drug, I think it is worth drawing graphs of levodopa equivalent plasma levels over the course of a day, with and without a dose of apomorphine, and with and without a dose delayed due to, for instance, eating protein.

I have written an app to do that. See:

Parkinson's Disease Measurement: PwP, surveys, trials, analysis

All the references to the literature are there.

(You can use this tool yourself. Just go to the web page, input details of your drug regimen and the program will draw the graph for you.)

Note that the pharmacokinetic parameters used are from a intra nasal version of apomorphine, and not from the sub-lingual version, Sunovion, but I wouldn't expect them to be greatly different.

In all the scenarios below the "on" threshold is set at 50 LED mg. This figure will vary greatly from person to person.

In the graphs below, the coloured lines show the contribution made by each of the doses. The black line shows the total at each time. The horizontal green line at 50 is the assumed "on" threshold.

Scenario 1. Five doses of 100mg levodopa/carbidopa taken at 0700, 1000, 1300, 1600 and 1900.

Plasma max (LED mg) = 127
On duration (min) = 760
Off duration (min) = 680

original.png

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Scenario 2. Five doses of 100mg levodopa/carbidopa taken at 0700, 1000, 1300, 1600 and 1900. But, due to, for instance, protein in the diet, the 1300 dose's action is delayed by 60 minutes and, then, only delivers 70% of the normal amount of levodopa.

Plasma max (LED mg) = 131
On duration (min) = 700
Off duration (min) = 740

delayedDose.png

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Scenario 3. As scenario 2, but additionally a 10mg dose of apomorphine is taken at 1400, because there is an unexpected "off".

Plasma max (LED mg) = 244
On duration (min) = 723
Off duration (min) = 717

apomorphine.png

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Obviously the answer will vary from person to person, but the question that this raises is:

Is the extra 23 minutes of "on" time worth the near doubling of levodopa equivalent peak plasma levels, and the effect that this may have on dyskinesia?

John