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DDC inhibitor v COMT inhibitor

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Old 06-24-2017, 09:20 PM   #11
johnt
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Thanks for the contributions from jeffreyn, soccertese, tupelo3, TexasTom.

(L=levodopa, C=carbidopa, E=entacapone. In what follows below L means L and not L/C.)

So, the question is: Why is there no L/E medication available? And to clarify once more, that's levodopa and entacapone, but without carbidopa.

A literature search is made difficult because "levodopa" is often used to mean "levodopa/carbidopa". However, I did find a few references to unambiguous L and L/E.

Ahlskog writes [1]: "entacapone in the absence of carbidopa/levodopa has no anti-parkinsonian effect".

I see it differently however: L/E is likely to be slightly more therapeutic than L, but it is overshadowed by L/C which is better. L/C/E is better still.

The method of working of both C, a DDC inhibitor, and E, a COMT inhibitor, is to prolong the peripheral life of the L that they are taken with. So, we are interested in the metabolism of L: the metabolic pathways, their relative power, their metabolites. The metabolic pathways of L are [2][3]:

DDC, 70%, Dopamine
COMT, 10%, 3-O-Methyldopa
TAT, ?, 3,4-Dihydroxphenylpyruvic acid
Tyrosinase, ?, Dopa quinone
PST, ?, Conjugation products

So, the effect of DDC is much stronger than COMT. Moreover, as others have mentioned DDC inhibitors reduce the amount of peripheral dopamine, which is good because peripheral dopamine causes nausea.

References:

[1] "The New Parkinson's Disease Treatment Book"
p142,
Ahlskog J., 2015

[2] Benserazide - ScienceDirect Topics

[3] "Encyclopedia of Movement Disorders, Vol 1"
ed. Kompoliti K. and Metman L.
2010
isbn:1237415X - Google Search

John
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Born 1955. Diagnosed PD 2005.
Meds 2010-Nov 2016: Stalevo(75 mg) x 4, ropinirole xl 16 mg, rasagiline 1 mg
Current meds: Stalevo(75 mg) x 5, ropinirole xl 8 mg, rasagiline 1 mg
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Old 06-26-2017, 10:48 AM   #12
Tupelo3
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Quote:
Originally Posted by johnt View Post
So, the question is: Why is there no L/E medication available? And to clarify once more, that's levodopa and entacapone, but without carbidopa.

A literature search is made difficult because "levodopa" is often used to mean "levodopa/carbidopa". However, I did find a few references to unambiguous L and L/E.

Ahlskog writes [1]: "entacapone in the absence of carbidopa/levodopa has no anti-parkinsonian effect".

I see it differently however: L/E is likely to be slightly more therapeutic than L, but it is overshadowed by L/C which is better. L/C/E is better still.

John
I think you all may be over-analyzing the question and the science behind the answer. I believe the answer is more simple. First, John is absolutely correct in that the early preclinical evidence was that L/E was less effective than L/C.

Second, most clinical trial protocol decisions are unfortunately not made purely about the science and perfect research design. Rather, investigators start at that point and then modify the design based on practicality and funding. When the initial trials were designed. it was very likely that the investigators, and Orion Pharma, knew if they wanted to compare L/E to L/C, they would first have to do dosing studies to find the right combination of L/E to equate it to L/C. Otherwise, they would have had to start the trials by having volunteers who were normalized on L/C and were randomized into the L/E test group, begin the trial with potential under or overdosing of L. That would have caused all kinds of side-effect problems. This wasn't practical when you consider that no one really believed there would be a significant improvement from L/E alone. So, Orion made the decision to just test E as an adjunct add-on to L/C and test the L/C/E combination for improvement over L/C alone. In reality, there really wasn't much benefit to L/C/E (some studies showed small improvement and some no improvement).

That's my thoughts and best guess on the question. I am working with Novartis (the original distributor of E) on another trial and have a meeting with them on Wed. I will ask them the question and see if anyone knows about or remembers the original trials and the decisions behind the design protocol.
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Old 06-26-2017, 04:21 PM   #13
johnt
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My interest in this topic is that in the era of personalized medicine I see an advantage in being able to get to any position in the levodopa, carbidopa, entacapone state space. It seems to me that there is a vanishingly low probability that both you and I are optimally treated with a levodopa:carbidopa ratio of exactly 4:1, and an entacapone dose of exactly 200mg per L/C dose.

As far as I understand it, L/C/E has a scaling factor of 1.33 compared to L/C, so roughly speaking a 75mg Stalevo tablet has the same power as 100mg L/C. So, there is good reason to believe that E, taken with L, has a role to play

I'd like to see more attention paid to increasing the half-life of levodopa at a molecular level, rather than at the delivery level, e.g. Rytary, an approach that for some patients gives less consistent results than immediate release L/C.

A short half-life leads to big swings in plasma levodopa concentrations, taking people into dyskinesia territory. So, for instance, for later stage patients with little endogenous dopamine production and reservoirs, to get a continuous "on" with a new dose taken every 3 hours and a levodopa half-life of 90 minutes requires peak levels 4 times higher than those needed just to reach the "on" threshold.

Finally, although I don't think that it well supported, the paper by Hinz et al. [1], which links carbidopa to increased PD death rates, must give a cause for concern.

References:

[1] "The Parkinson’s disease death rate: carbidopa and vitamin B6"
Marty Hinz, Alvin Stein, and Ted Cole
Clinical Pharmacology, 2014
The Parkinson’s disease death rate: carbidopa and vitamin B6

John
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Born 1955. Diagnosed PD 2005.
Meds 2010-Nov 2016: Stalevo(75 mg) x 4, ropinirole xl 16 mg, rasagiline 1 mg
Current meds: Stalevo(75 mg) x 5, ropinirole xl 8 mg, rasagiline 1 mg
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Old 08-22-2018, 08:21 PM   #14
johnt
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I'd like to look at a related question: why don't we inhibit all the metabolisers of levodopa?

I'm posting in this thread, rather than start a new one, because a lot of the background information is contained in previous posts to this thread. In particular (in Post 11) the following table showing 5 metabolism routes for levodopa, not just the normal two: DCC, COMT)

DDC, 70%, Dopamine
COMT, 10%, 3-O-Methyldopa
TAT, ?, 3,4-Dihydroxphenylpyruvic acid
Tyrosinase, ?, Dopa quinone
PST, ?, Conjugation products

At first sight, inhibiting metabolisers which are responsible for a small part of the metabolism seems likely to have only a small impact. But, depending on where you are starting from, this reasoning is incorrect. Suppose that you have two metabolisers A and B responsible for 80% and 10% of metabolism respectively. Then introducing B after A reduces the rate of metabolism from where we are now by half. For instance, going from L/C to L/C/E has this impact [1]:

"Compared with conventional levodopa, the pharmacokinetic profile of levodopa with dual enzyme inhibition [L/C/E, Stalevo] is markedly improved, increasing the half-life of levodopa by up to 85% and the bioavailability of the drug by 35% in plasma".

Given this, from where we are now, inhibiting the other levodopa metabilisers, is likely to have a big effect.

Why is this important? Not to save on the size of the dose. But, to extend the half-life, thus cutting down the variability of plasma levels, which are thought to contribute to dyskinesia.

[1] "Optimizing levodopa therapy for Parkinson’s disease with levodopa/carbidopa/entacapone: implications from a clinical and patient perspective"
D. Brooks
Neuropsychiatric Disease and Treatment, 2008
Optimizing levodopa therapy for Parkinson’s disease with levodopa/carbidopa/entacapone: implications from a clinical and patient perspective

John
__________________
Born 1955. Diagnosed PD 2005.
Meds 2010-Nov 2016: Stalevo(75 mg) x 4, ropinirole xl 16 mg, rasagiline 1 mg
Current meds: Stalevo(75 mg) x 5, ropinirole xl 8 mg, rasagiline 1 mg
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Old 07-10-2019, 07:28 PM   #15
johnt
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Bumping this up in the light of the recent discussion on Albert's thread on the use of grapefruit juice as a CYP3A4 inhibitor.

Matabolism of L-Dopa

John
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Born 1955. Diagnosed PD 2005.
Meds 2010-Nov 2016: Stalevo(75 mg) x 4, ropinirole xl 16 mg, rasagiline 1 mg
Current meds: Stalevo(75 mg) x 5, ropinirole xl 8 mg, rasagiline 1 mg
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