We see two PwP, both of the same age and both diagnosed at the same time, but one doing well and the other doing poorly. And what we usually think is "we're all different". Although correct, this way of thinking may be covering up differences in the effectiveness of our treatment regimen (drugs, supplements, DBS, exercise etc.).

Let's try to pin down what I'm thinking of. Suppose we had access to the world's best doctors who, if necessary, we could see at a moment's notice; and, suppose that we could use, without financial limitations, any therapy that is available now; then, how would we be doing compared to how we are doing?

Suppose also that we had perfect measures of how we are actually doing, call this A, and how we would be doing if given the perfect treatment, B. Let's set the measures up so that a higher figure is good. And, let's make it clear that we're concerned with the individual, not the average. For instance, two people could have the same treatments but, because their underlying needs are different, they could have different B values.

Let's create a measure, Q, to represent the quality of our treatment, defined as A divided by B. Then if we had a Q score of 1, it would indicate that we had the best possible treatment, and a Q score of 0 would indicate that we were dead.

A Q score of 0.9 would indicate that we're doing almost as well as is possible with existing technology. With such a limited up-side, it would suggest that rather than hone our regimen, we should be interested in research.

A Q score of 0.5 would suggest that our treatment could be considerably improved: that we should probably be more interested in ways to improve the quality of our treatment, rather than research into new therapies.

I'd be grateful to hear from others about the quality of their treatment.

Although it's ill-defined, my very rough estimate of my Q score is 0.7.

John

Okay, I'll go first. I would say that 0.9 is my very rough estimate of my Q score.

I would think that those in the early stages of PD (like me) would tend to have higher Q scores. Arguably, all of the currently available treatments provide only symptomatic relief, and they tend to work best for those whose symptoms are less severe (e.g. those in the early stages).

As you predicted, my focus is mainly on research, but it's more specific than that. My main interest is research in the areas of neuroprotection and neuroregeneration (i.e. research in the area of symptomatic relief is of less interest to me). This is probably a bit short-sighted of me, since I will be needing better symptomatic relief as my disease progresses. I guess the optimist in me is assuming that the neuroprotection or neuroregeneration research will be successful before then!

For those PwP in the later stages, I think that research in general might be of less interest, mainly because it's more likely that the benefits of current research efforts will come too late for them. But it's also a bit more complicated than this. For example, for some PwP in the later stages, I would think that neuroprotection without adequate symptomatic relief might not be considered a result worth having. So for them, the measure you've called "B" (perfect treatment) might be a bit harder to determine (in the future).

This post wants to explore the implications of having only a limited number of pill strengths on the optimisation of Parkinson's symptom control. Although similar results apply to all Parkinson's drugs, this post focuses on Sinemet (carbidopa - levodopa), and in particular instant release preparations.

Immediate release Sinemet in the US comes in the following three strengths [1]:
"SINEMET 25-100, containing 25 mg of carbidopa and 100 mg of levodopa.
SINEMET 10-100, containing 10 mg of carbidopa and 100 mg of levodopa.
SINEMET 25-250, containing 25 mg of carbidopa and 250 mg of levodopa."

Immediate release REQUIP comes in seven strengths [2]:
"0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, and 5 mg"

Why are there more strength choices for REQUIP (ropinirole, a dopamine agonist) than Sinemet?

There seems to be a culture of pill splitting in the US. It is not so common in the UK. Interestingly, a 12.5mg carbidopa / 50mg levodopa pill is available in the UK. So, let's assume that in the US halving, but not quartering, is practiced on the 100mg pill only; and in the UK no splitting occurs. Either way the step size for any dose is 50mg of levodopa. (We will ignore, for now, the two-dimensional effect of having the carbidopa to consider as well. What if for a particular person a carbidopa/ levodopa ratio of 1:5 or 1:3 is better than the 1:4 and 1:10 ratios that are available?)

The analysis assumes there is an optimum dose of levodopa, which varies from person to person, and from time to time. We have two problems: finding out for a particular person what the optimum dose is; finding a way to administer the optimal dose.

Given the short half-life of levodopa (about 90 minutes) and the rough and ready approximations that we are making, we can focus on a single dose, rather than the whole daily regimen.

The strength of a dose is usually decided by starting from a low initial dose, titrating up until an acceptable level of symptoms is reached.

We will illustrate the effect of having only a small number of strengths of levodopa options on a person requiring a dose of 150mg (repeated at least three times per day). A step size of 50mg, implies that the most unlucky people are one third out and the average person will be almost 17% away from the optimum dose.

The step size error is only one of a number of sources of error, so the total error is likely to be larger when we take into account other considerations, such as: whether the optimal dose was correctly obtained and is still correct given the progression of the disease, the pill strength matches the advertised strength, the carbidopa ratio is optimal, diet is optimal, etc..

A dose 17%, or whatever, away from optimum does not necessarily imply that the effect on symptom control is also 17%. It can be more, or it can be less. If we are targeting the "on"/"off" threshold and no more, a 17% reduction from the optimum dose could lead to the threshold never being released. Alternatively, if we are above the threshold a dose larger than that required might lead to a small increase on "on" time, but this might come at the cost of having the undesired side-effect of taking us into dyskinesia.

The way easiest way to reduce the problem is to have more pill strengths. Alternatively, if it is thought that exact dose strengths are desirable, e.g. a dose of 57mg of levodopa is required, and cannot be substituted with a dose of 50mg, we need another mechanism. This can be achieved for immediate release drugs (but not controlled release drugs) by dispersing the pill in vitamin C, and measuring off the required amount.

References:

[1] https://www.merck.com/product/usa/pi...sinemet_pi.pdf
dated 07/2014

[2] https://www.gsksource.com/pharma/con...UIP-PI-PIL.PDF
dated 5/2017

John

Medication for Parkinson's is, albeit after some delay, often directly felt by a PwP. This is especially true of levodopa-carbidopa because of both levodopa's effectiveness at reducing the symptoms of PD and its short half-life. This makes the actual, as opposed to the nominal, size of the dose important for PwP.

Although general in its coverage, and not being specifically about Parkinson's, a paper by Paveliu et al. raises some interesting issues.

Batch/batch variance: Pavelui writes [1]
"Various pharmacopoeia admit variations of + / -5% margin in active ingredient between the products [from] the same batch".

Brand/generic: based on work done by the FDA back in 1999:
"The observed mean difference between the innovator's product and the generic product for AUC (0-t) was ± 3.47% (SD, 2.84), for AUC (0-Inf) it was ±3.25% (SD, 2.97), and for Cmax it was ± 4.29% (SD, 3.72). ... So the concerns seem to be unjustified."
I think we should be concerned by a 4% average difference, especially because the actual difference could be higher.

Generic/generic variance. The FDA requirement for a generic is that the 90% confidence interval for its values of certain pharmacokinetic parameters lie within a range of 80% to 125% of the original. Note: this is not the same as saying that 80% or 125% is acceptable. This is because there will always be some variability leading to the confidence interval not having zero width. But let me make a gross approximation and say that you could get two generics, one with 90% of the pharmacokinetics of the original and another one with 110% of the original. So someone stepping from one generic to another, different generic could face a 20 percentage point difference.

Reference

[1] "Generic Substitution Issues: Brand-generic Substitution, Generic-generic Substitution, and Generic Substitution of Narrow Therapeutic Index (NTI)/Critical Dose Drugs"
Marian Sorin PAVELIU, MD, PhD,a Simona BENGEA, MD, PhD,a and Fraga Silvia PAVELIU, MD, PhDa
Maedica (Buchar) Jan, 2011
Generic Substitution Issues: Brand-generic Substitution, Generic-generic Substitution, and Generic Substitution of Narrow Therapeutic Index (NTI)/Critical Dose Drugs

John

I've just come across a paper by Gasser et al. [1] that covers much the same ground as the previous reference, but the Gasser paper is specific to Parkinson's. It deals with variations in Madopar and its generics. Madopar is made by Roche. Madopar is commonly used in Europe.

Madopar is a formulation of levodopa and benserazide, typically in a ratio of 4:1. It differs from Sinemet in that it uses benserazide as a AADC inhibitor rather than carbidopa.

Source , Mass , Levodopa, Benserazide hydrochloride
----------------------------------------
Tab Roche, 267-283, 95-105, 27.1-29.9
Generic 1, 265, 92.4, 30.9
Generic 2, 284, 98.2, 27.8
Generic 3, 283, 94.4, 26.9
Generic 4, 284, 95.5, 28.8
Values in mg.

Gasser writes:
"Switching back and forth between brand and generic, or even between generics, is a recipe for problems that may cancel out the savings achieved with the cheaper drug."

Reference:

[1] "Pharmaceutical quality of seven generic Levodopa/Benserazide products compared with original Madopar® / Prolopa®"
Urs E Gasser, Anton Fischer2, Jan P Timmermans and Isabelle Arnet
BMC Pharmacology and Toxicology, April 2013
Pharmaceutical quality of seven generic Levodopa/Benserazide products compared with original Madopar(R) / Prolopa(R) | BMC Pharmacology and Toxicology | Full Text

John

John,

Care does vary. My MDS sets aside 30 minutes per appointment, and likes to see three month follow ups (sooner when ramping & new; less often when stable and doing fine). She is fantastic.

I highly recommended her to everyone in my Boxing Class. Well, she has a full practice and not seeing any new patients.

Everyone who switched from Doctor X to her had had improvements. She is also proactive about Exercise, Diet, and referring people to a sleep specialist (I have central apnea issues, and need my CPAP). Doc X doesn't believe in Exercise and pretty much tells everyone there is nothing to be done.

One issue I've personally seen was Doc X kept ramping up medication levels as "Parkinson's is progressive". My Doc had people REDUCE their medication levels to "acceptable amount of tremor". Some it to be expected, it's a balance. Folks who reduced were doing my better!

If your Doc thinks a 10 minute visit once a year is all you need, find another doc (MDS!)

We owe to ourselves to be our own advocates.

Battle each issue as it comes!

Tom, you're right about the importance of the doctor. Adjusted for the type of patient they are working with, it would be interesting to have statistics for each doctor showing how well their patients are doing.

John

Hi Tom et al,

I have certainly found this to be true and feel it is an extremely important statistic that deserves much attention as it waxes contrary to traditional allopathic protocol. How do you explain this?

Kind regards,
MD