See the diagram below:



A simple model using the pharmacokinetic properties of levodopa suggests that when the drug is at its highest concentration, about a hour after being taken orally, plasma levels are approximately 4 times higher than is immediately required.

The model makes many simplifications. Notably it does not capture that levodopa's pharmacokinetic parameters will vary from time to time and from person to person. Nevertheless, the model does seem to reasonably reflect my experience of using levodopa, and the model does seem to show some interesting features of levodopa therapy.

When taken orally a dose of levodopa (taken with carbidopa) progresses through the stomach into the upper intestines where it is gradually absorbed. Peak plasma levels are typically found about 60 minutes (TMAX) after the drug is taken. Thereafter, plasma levels halve about every 90 minutes (THALF).

In broad strokes, the pharmacodynamic effect of this on us is that immediately after taking a dose there is no benefit from the levodopa. Then, after about 15 - 60 minutes the drug kicks in, often quite suddenly, and we go from "off" to "on". It is as though there is a threshold that needs to be crossed to get any benefit. After this we can expect about three to four hours of "on" time before, again often quite suddenly, we go "off".

For a person who has no significant endogenous production and storage of dopamine, a major part of the movement process is being controlled by the exogenous levodopa. Therefore, the only way to stay "on" is to keep plasma levels above the threshold level. To do this, one dose must be responsible for 3 to 4 hours of "on" time. The only way that this can be done using standard delivery mechanisms is to overshoot the threshold. Taking us just to the threshold gives us only an instant of "on" time as the concentration immediately begins to drop. Taking us to twice the threshold gives us: half the time to maximum dose (about 30 minutes) plus one half-life of duration (about 90 minutes) for a total of 120 minutes of "on" time. Taking us to four times gives us three quarters of the time to maximum concentration (about 45 minutes) plus two half-lives of duration (about 3 hours), for a total of about 225 minutes of "on" time.

For someone still producing and storing dopamine the overshoot will be reduced.

What are the effects of having such high levels of levodopa, which fluctuate through the course of each dose? Why is the norm not to take more frequent, but smaller doses?

John

I've had those same questions.

johnt said: "Why is the norm not to take more frequent, but smaller doses?"

One answer to this question is that taking more frequent but smaller doses might be considered by some to be too onerous, both in terms of the larger number of doses, and the increased difficulty of timing the doses in relation to food intake.

Here is the story behind my answer, for those with time to spare.

About a year ago my neuro thought my tremor could be improved by increasing my dosage of Madopar 125 from 3 tablets per day to 4.5 tablets per day. When I tried the new dosage I experienced dystonic dyskinesia in my right foot (it started about half an hour after I took the new dose, and lasted for about one hour). I reduced the dosage back to 3 tablets per day but the dyskinesia still occurred. I phoned the Parkinson's nurse for advice and she said it was up to me to choose the dosage, based of whether it was the tremor or the dyskinesia which bothered me the most. I asked her whether it was worth me trying a dosage of half a tablet 6 times a day, and she said "Too onerous!" But I did it anyway, and the dyskinesia stopped occurring. About 6 months ago (after my last visit to the neuro) we increased the dosage to three quarters of a tablet 6 times a day, and the dyskinesia has not re-occurred.

Taking a dose 6 times per day may seem bothersome, but so far it has been a breeze. We've set up an alarm on the screen-phone to go off at 2.5 hour intervals starting at 8am. When I am out and about I wear a bum bag containing a small bottle of water and some half tablets and quarter tablets. I'm also lucky in that, at this early stage (diagnosed June 2015), when I eat doesn't seem to have any noticeable effect on the medication. I can also miss a dose by half an hour (or even one hour) and, at this stage, this also seems to have no noticeable effect.

Hi John and Gerry,
Good point about smaller dosages of levodopa with less of an interval.
I tend to take less and it works okay of a day....not always but mostly!
I take the dosage in a 24hr period that my neuro recommends only thing is I have different ideas when it comes to timing!
He says 100mg every 3 hrs where I tend to take 50mg every one and a half hrs during the day and early evening.
Best wishes.

Thanks for your comments.

To draw a graph of your levodopa equivalent plasma levels taking into account the size and timing of your dose(s) you can use:
Parkinson's Disease Measurement: PwP, surveys, trials, analysis

I've been given the "too onerous" line by medics too. I say that you must have a very mild form of the disease for it to be too much effort to take an extra dose if that is more optimal. I think a better argument is one of compliance: the more doses you have, the higher the chance of missing one (but the smaller the consequences).

Rather than having to halve and quarter the pills, why not have a range of pills with smaller doses?

I've tried dissolving Stalevo in Vitamin C. That allows you to draw off whatever dose you want.

John

johnt said: "Rather than having to halve and quarter the pills, why not have a range of pills with smaller doses?"

My Madopar 125 tablets are double scored, and I have a pill cutter. It takes next to no time to create halves and quarters, and I've never had one crumble. But I appreciate the suggestion. Thanks.

bigger doses don't help, more frequent dosing does.
that's why entacapone, mao-b inhibitors are added in hopes extending how long an adequate blood concentration of l-dopa can be maintained. getting enough l-dopa into the blood is usually not the problem, that's the easy part. the hard part is keeping it constant in the advanced patient - yopd'ers are still producing their own l-dopa and protecting it from being destroyed in the brain, i.e. they still have normal l-dopa production so the oral l-dopa you take is just a "top up, which is not possible 24hrs a day with current oral medication imho which is why l-dopa pumps are now in play, and i think they actually use more l-dopa than when a patient uses pills, go figure

in the book "UNDERSTANING PARKINON'S DISEASE" by richard b.rosenbaum, pg 99, where he is describing the early research where patients were given l-dopa, some OVER 10 GRAMS - carbidopa hadn't been invented yet(?) - and this was a surprise that such a high dose was needed to be effective when it was estimated that the brain only needed 7.5mg of l-dopa assuming it could diffuse to the parts of the brain where it is needed.

so what explains the "wall" where increasing the dose doesn't help? must be that the there just aren't enough brain cells left that produce the enzyme that converts l-dopa to dopamine to outpace the enzymes that break down l-dopa. so all that extra l-dopa in the blood doesn't help, once it gets into the brain it has to diffuse where it's needed so the limiting factor much diffuses to where it is needed and how fast it can be converted to l-dopa, all the while being broken down by mao-b? i'm sure it's much more complicated than that. i picture it like you have a huge crowd waiting to get into a concert hall with set number of entrances and set number of chairs, once you saturate the entrance and chairs, doesn't matter what how high big the crowd becomes add to that the fact that you have "thugs" (enzymes) taking people (l-dopa/dopamine) out of the line.

think about the fact that 14mg of requip = 1000mg or more of C/L and assuming they are equal in 1 l-dopa molecule = 1 requip molecule, just shows how little 'l-dopa is needed by the brain.

so that's why you commonly read C/L doses above 250mg aren't any better.

of course OFF's would potentially be less of a worry as would eating if the faster acting inhaled l-dopa and subilngual apomorphine get approved, who cares if a month's supply will equal a mortgage payment

Thanks for the posts soccertese. You have addressed John's first question, whereas my post only addressed his second question.

soccertese said: "yopd'ers are still producing their own l-dopa..."

I may be splitting hairs here again, but I think we're more accurately described as "early-stage PDers" rather than "young-onset PDers". After all, you can be both a young-onset PDer and an advanced-stage PDer at the same time.

I take 100 mg every 1 and 1/2 hours during the day and one at midnight. I adjust the timing a bit depending on activity level.

year 13 since diagnose - still moving