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