Weight affects the effect of a dose
 

In the reports of studies on rats, you see dosage defined in terms of weight, e.g. 100 mg/kg.

Is this always done in human trials?

How often is body weight considered in the day to day prescribing of PD drugs?

Back in 2002 Zappia et al, reported on this effect [1]:

" ... a greater percentage of women showed LD peak-dose dyskinesias compared with men. Our findings suggest that lighter patients with Parkinson's disease probably receive a greater cumulative dosage of LD per kilogram of body weight during long-term treatment, because in clinical practice, LD is administered without any adjustment of the dose to body weight. This could explain gender differences for the development of LD-induced peak-dose dyskinesias observed during the course of the disease."

It is possible that for drugs targetted at the brain (e.g. carbidopa is used to allow more of the levodopa to get into the brain) that brain weight should also be considered.

References:

[1] Clin Neuropharmacol. 2002 Mar-Apr;25(2):79-82.
"Body weight influences pharmacokinetics of levodopa in Parkinson's disease."
Zappia M1, Crescibene L, Arabia G, Nicoletti G, Bagalà A, Bastone L, Caracciolo M, Bonavita S, Di Costanzo A, Scornaienchi M, Gambardella A, Quattrone A.
http://www.ncbi.nlm.nih.gov/pubmed/11981233

John

John,

I have often thought this to be the case. Surely, like any other drug, weight affects metabolism or pharmacodynamics, yet I have seen maybe two articles at most that even ask this question let alone ask the bigger questions you do.

In my experiences, not one doctor has ever broached weight. It seems like once I started levodopa I called the shots in my dosage. This, to me, underscores how little is by doctors other than trial and error in the treating our PD. Not their fault; that is just how it is.

I have started two clinical trials and not surprisingly, weiight is not all considered.

This, of course, begs the question...how can the amount of levodopa we take be at all be a measure of disease severity? It cannot, yet study after study uses it as a yardstick because it is all they have. Any research using dosage as a measure seems fundamentally flawed to me. My current MDS who has managed clinical research for over 20 years told me that when levodopa doses have been tracked for studies; there is absolutely no pattern or relation to disease severity or longevity. He says the data is all over the place and one would be surprised that it even works at all from a research control perspective.

This is why we are in dire need of bio-markers and imaging to not only better treat patients but to also give the research the validity and reliability it so sorely needs.

Laura

"My current MDS who has managed clinical research for over 20 years told me that when levodopa doses have been tracked for studies; there is absolutely no pattern or relation to disease severity or longevity"

i find that hard to believe. the sinemet honeymoon ain't a myth. neuros toolkits are very lacking as we advance, i agree 100% with that.

Let's see if we can find any empirical evidence of an association between body weight and the amount of levodopa required.

Here's a scatter plot of PDMeasure data showing, for each gender, the levodopa equivalent daily dose and the number of years since diagnosis.

Attachment 8323

Statistics for men are:
n=24
mean years since diagnosis = 4.97
mean LEDD = 413mg
r=-0.045 - this could be caused by an outlier
assumed mean weight=190lb - based on Wikipedia[1] and UK, US bias in PDMeasure

Statistics for women are:
n=14
mean years since diagnosis = 3.98
mean LEDD = 288mg
r=0.671
assumed mean weight=158lb - based on Wikipedia[1] and UK, US bias in PDMeasure

Note that in this sample women are on average more recently diagnosed (by 1 year) and have a lower LEDD (by 125mg). If we scale up the women's figure to take account of the different average body weights of the genders, 288mg goes to 288*190/158=346mg. There's insufficient data to get statistical significance, but, in my opinion, the data is more supportive of the notion that the titration process gets people regardless of weight to the right place for them, rather than lighter people are being generally over medicated. But that certainly does not mean that no one is over medicated.

Laura raises two points:

Can LEDD values be used to estimate progression?
The men's figure suggests not, but there's a particularly prominent outlier that may be distorting things. However, the women's figure shows a moderate correlation between LEDD and years since diagnosis which is, in turn, given the progressive nature of PD, probably linked to progression. Correlation is not transitive. But it seems reasonable to assume LEDD is associated weakly with progression. Further work is needed to pin down the direction of causality.

The importance of biomarkers.
I agree with that, but feel that not enough is being made of the objective symptom measurement tools that we already have. If the will had been there, we could have mass data collection by now.

References

[1] http://en.wikipedia.org/wiki/Body_weight

John