DDC inhibitor v COMT inhibitor
 

As I understand it, there are two distinct mechanisms which have been used to reduce the peripheral metabolism of levodopa:

- DDC inhibitor (e.g carbidopa). Carbidopa [1] "inhibits aromatic-L-amino-acid decarboxylase (DOPA decarboxylase or DDC), ... an enzyme important in the ... biosynthesis of L-DOPA to dopamine (DA). DDC exists both outside of (body periphery) and within the confines of the blood brain barrier."

- COMT inhibitor (e.g. entacapone). Entacapone [2] "is a selective and reversible inhibitor of the enzyme catechol-O-methyltransferase (COMT)... When taken together with levodopa (L-DOPA) and carbidopa, entacapone stops catechol-O-methyltransferase from breaking down and metabolizing levodopa, resulting in an overall increase of levodopa remaining in the brain and body."

So, there's Sinemet (= levodopa + carbidopa) and Stalevo (= levodopa + carbidopa + entacapone). But, I've never seen levodopa + entacapone (i.e. without carbidopa). Why is this?

References:

[1] Carbidopa - Wikipedia

[2] Entacapone - Wikipedia

John

My understanding
 

My understanding regarding DDC inhibitors is as follows:
- if you don't add a DDC inhibitor (i.e. carbidopa/benserazide), you need to use a much larger dose of levodopa, in order for sufficient levodopa to make it into the brain;
- such large doses of levodopa cause unwanted side effects (e.g. nausea).

My understanding regarding COMT inhibitors is that their main function (in PD treatment) is to (try to) stop COMT from breaking down dopamine in the brain.

Jeffreyn,

Thanks for your prompt reply.

I agree when you write:
"- if you don't add a DDC inhibitor (i.e. carbidopa/benserazide), you need to use a much larger dose of levodopa, in order for sufficient levodopa to make it into the brain;
- such large doses of levodopa cause unwanted side effects (e.g. nausea)."

You write:
"My understanding regarding COMT inhibitors is that their main function (in PD treatment) is to (try to) stop COMT from breaking down dopamine in the brain."

I'm not familiar with this process. However, what you describe is the role played by MAO-B inhibitors (e.g. rasagiline) [1].
"Selective MAOB inhibitors ... preferentially [inhibit] MAOB, which mostly metabolizes DA. If MAOB is inhibited, then more DA is available for proper neuronal function, especially in Parkinson's Disease.

In a recent doctorial thesis [2] I've found a reference to the effect of levodopa plus entacapone without carbidopa:
"That the Cmax and AUC of levodopa in both CSF and blood increased significantly when additional entacapone was given alone and in combination with carbidopa. The increase was more evident when entacapone was combined with carbidopa."

Reference:

[1] Monoamine oxidase B - Wikipedia

[2] "Levodopa pharmacokinetics-from stomach to brain"
Maria Nord,
Dissertation, Linkoping University, 2017
https://liu.diva-portal.org/smash/ge...FULLTEXT01.pdf

John

John, it's not just levodopa that the COMT enzyme acts on, it's all the catecholamines as well.

From Wikipedia (see link):
"Catechol-O-methyltransferase (COMT) is one of several enzymes that degrade catecholamines (such as dopamine, epinephrine, and norepinephrine), catecholestrogens, and various drugs and substances having a catechol structure."

Catechol-O-methyl transferase - Wikipedia

In regards to your main point, if you had a drug which contained just levodopa and entacapone, you wouldn't be able to stop the DDC enzyme from converting a lot of the levodopa into dopamine, before the levodopa made it into the brain. The dopamine produced in this way would be of no benefit to the PwP, since dopamine cannot pass through the blood-brain barrier.

i don't think carbidopa and entacapone pass the BBB. if carbidopa entered the brain very little l-dopa would be converted to dopamine in the brain. this feature made carbidopa so attractive and reduced the l-dopa dosage from over 10grams and impractical to use to treat pd for the masses to what it is today.


entacapone also doesn't cross the BBB which makes it less potent than Tolcapone (tasmar) which i think is no longer used in the U.S. over liver toxicity risks and the need to monitor that.

Medscape: Medscape Access
Entacapone is highly protein bound, approximately 98%, with a limited body distribution.[42,44] It has poor brain penetration and predominately peripheral effects, although it may exhibit central effects if given in high doses.[

ST is correct, entacapone has limited ability to pass the BBB. Tolcapone had significantly better absorption in both the body and brain.

My new understanding
 

Okay, it seems clear now that my understanding of the role played by COMT inhibitors was faulty.

My new understanding is as follows:
The main purpose of COMT inhibitors (in PD treatment) is to (try to) stop the COMT enzyme from breaking down levodopa (mainly outside of the brain).

Johnt, sorry for derailing your thread with my misunderstanding regarding the role of COMT inhibitors. Soccertese and Tupelo3, thanks for helping to clear up that misunderstanding.

John's initial question still stands: why isn't there a drug which just contains levodopa and entacapone?

As I said earlier, my understanding is as follows:
"If you had a drug which contained just levodopa and entacapone, you wouldn't be able to stop the DDC enzyme from converting a lot of the levodopa into dopamine, before the levodopa made it into the brain." Which means you would need to use a lot more levodopa, which means you would get more severe side effects (e.g. nausea).

Is my understanding correct? Are there any other reasons?

Levodopa is the active ingredient.
Carbidopa is a buffer to help prevent nausea (too much Levodopa triggers the brain into thinking the stomach has nausea, but it is all in the brain).

Hence 25/100 is common Carbidopa/Levodopa ratio. You can find 10/100 C/L formulations, but more often people have nausea issues.

Cabidopa by itself is available as a separate medication. USA trade name is Lydosyn. Often as 25mg, taken in addition with 25/100 Sinemet

Comtan just helps the levodopa stick around longer. So if C/L starts to wear off after four hours, your doc may add Comtan to see if C/L benefits last six hours.

I'd never heard of Lydosyn (i.e. a drug which contains only carbidopa).

So then, back to my own question from above: are there any other reasons why there isn't a drug which contains just levodopa and entacapone?

I guess one possible reason might be that there just isn't a big enough market for such a drug. Maybe you can just about do all you'd want to do, using a combination of Sinemet, Comtan and Lydosyn.

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

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.

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

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

Bumping this up in the light of the recent discussion on Albert's thread on the use of grapefruit juice as a CYP3A4 inhibitor.

https://www.neurotalk.org/parkinson-...lism-dopa.html

John