Optimising LD timings

[ZebraDoodle]

Hi all,

I wanted to share the results of a ‘thought experiment’ I’ve been playing with and get feedback on some inevitable follow-on questions.

Just to be clear I'm not advocating anyone does what I describe below - I'm posting it for feedback / discussion purposes only (and for someone to show me where it's already been done - and better - (but, hey, I enjoyed the journey :)).

Scenario: A PWP experiencing wearing-off of LD/CD is attributing this to the somewhat arbitrary default of evenly spaced doses suggested by the neurologist. What is the optimal medication schedule - one that reduces the variability of the levodopa equivalent dose (LED) value during the working day (~9:30am-5:30pm)? Can you create a ‘virtual LD pump’ dosing profile?

Based on my understanding of LED from the very useful parkinsonsmeasurement.org/t... the LED for LD/CD IR at evenly spaced doses could swing around during the day and the downward slopes could cause various, significant, wearing-off events during the day.

Assumptions:

A PWP with enough residual self-produced dopamine to ~1030, then a need for boost >=0.6LED during the working day.

Baseline medication schedule: With three LD/IR (100/25) (one at 0900, 1200 and 1500) you get the following profile with these spikes (and IMHO three ‘sharp’ wearing-off periods):

[FIGURE 1 - attached at end]

Medication ‘solution space’ constraints: Permutations of LD/CD 100mg IR and LD/CD 100mg CR up to a combined total of four pills.

Using the reported average blood plasma level profiles from the above website for these two medications I wrote a bit of code to find the optimum dosage times that aims for a minimum of 0.6LED and to minimise the standard deviation during the working day time period. (I did this a few months ago so need to double-check the nuances - if I don’t post text in this state I never will!)

This suggested the graph below (where the red line is 100mg LD/CD IR (0907) and green, blue and yellow lines are now 100mg LD/CD CR (at 1050, 1256 and 1524)). (Timings to the minute are a bit academic but hey this is a thought experiment :)) There's certainly less erratic LED levels.

[FIGURE 2 - attached at end]

Now the questions I have are:

(a) what assumption can you make about lunch? Do you assume that for the lunch window (30 mins before and 60 mins after) there is no absorption? Or do you assume no lunch?

(b) does anyone have any absorption data for dispersible LD? Could this be a way to further smooth out the profile with sips of a LD drink? (Don’t want to go too much off-topic on that one though)

(c) this is obviously a hypothetical situation for a non-existent ‘average’ PWP at a point in their 'journey' who wants a steady 0.6LED for a given window on an ‘average’ day. It would be interesting to try adding some noise factors (e.g. lunch, timings, LD absorption rates & half-lives) – to create an uncertainty profile to overlay. Does anyone have any suggestions what reasonable uncertainties might be? (I still need to read the references in the above website – just thinking ahead really))

To reiterate I'm not advocating anyone try what I describe - I'm posting it for feedback / discussion purposes only.

Thanks in advance for any suggestions / feedback.

[ZebraDoodle]

[Only way I could find to post the figure]

Figure 1 - Baseline LED profile

[ZebraDoodle]

[Only way I could find to post the figure]

Figure 2 - 'Smoothed' LED profile using optimised timings

[Jana86 in reply to ZebraDoodle]

I attempted to use the same tool (parkinsonsmeasurement.org) to figure out the same problem. I came away convinced that fruit for breakfast and vegetables for lunch (along with accepting that only 7 AM to about 3 PM would resemble functional life) was the best I could do. For me, the impediment to uptake was what I ate, not when and the uptake challenge increased as the day went on. . After 12 years of stomach aches, and the last 5 in which my life became completely unpredictable due to erratic uptake, I am opting for DBS.

The measurement tool is great at validating what you already know. The off time and dyskinesia were visible and anchored in reality. May sound odd...but the experience before measurement seemed punishing and random. I am choosing DBS because I can't control the dosage using the pills we have. A pump is interesting but the problem you raise seems to carry over to dosage control in any setting. Since almost any PwP will say that their need for dopamine corresponds to stress levels, other health issue spikes, exercise intensity, level of fatigue, and some say the weather, it would seem a more responsive, customizable delivery system would be at the top of the list for invention if you want to improve QOL for PWP.???

[ZebraDoodle in reply to Jana86]

Thanks - interesting point re: stress / other illness/ environmental factors.I think that reinforces the argument for this type of approach but see what you mean about the potential for this to break down with progression.

But back to the original point If you have a higher, smoother, LED level then presumably that would make you more resilient to external stressors? Going to have another look at it again when I get the chance. I tried boosting the minimum LED to 0.8 (from memory) and the best answer seemed to be to add in another LDCR. Am interested to know if anyone has an opinion on this approach to reducing wearing-off vs adding in Stalevo? (Another thing to try on the tool).

[LAJ12345]

it’s kind of what we do with hubbies IR madopar meds. More and close together in the morning and spaced further apart in the evening.

If you are making your pump to be controlled by an app you could allow people to enter extra information about the level of stressful tasks or extra exercise they plan for the day. But then they might keep increasing the dose too often. And the doctors would have to prescribe a fixed amount so the monthly supply might run out.

Also my husband gets more anxious on higher amounts of levodopa which makes him more stressed as he things he’s getting worse.

There seems to be 2 types of people. Those that feel better on more and others that feel worse.

[ZebraDoodle in reply to LAJ12345]

Agree. I’m interested in this from a personal perspective and because it’s a bit of a puzzle. No plans to build anything. It would be interesting to know if there’s some signal that could be used to predict a better ad-hoc schedule. But agree in this hypothetical situation that the neuro would basically set the budget of pills and that’s what you have to work with.

[LAJ12345 in reply to ZebraDoodle]

I think some people still produce quite a lot over night so doses should be more and closer together in the morning and less and further apart at the end of the day. That works best for my husband

[Esperanto in reply to LAJ12345]

That doesn't seem quite logical. My experience is that I did indeed start producing dopamine again at night. Especially after improved sleep, this was the case. The result was actually that I could take less C/L and even skip the first morning dose, while in an earlier worst stage it was higher and closer to the next dose.

[LAJ12345 in reply to Esperanto]

It does really because although they produce it over night it isn’t quite enough to be of much use for long once you wake up.

Most people don’t take their meds in the middle of the night regularly like they do during the day so it might have been 8 hours since the last dose of medication by the morning. The naturally made stuff can maybe last the night and 1/2-1 hour when you wake up but the lowest point of the natural cycle is around mid day so it drops off rapidly .

So if you load up the first few doses it fills in the trough of the natural cycle, then take less in the evening as the natural cycle starts to kick in again.

Of course it depends on how much is still being made by the body.

[Esperanto in reply to ZebraDoodle]

To be able to respond ad hoc and enable dynamic dosing, you need a practical measurement method that constantly observes your PD symptoms. I was hoping to find that with my iwatch, but I haven't come across the right app yet. Therefore, I still use my finger tapping method, which quickly and accurately shows my potential C/L needs. If I forget to tap, I often have a backup through my partner, who notices when I need medication…

It doesn't always have to be a hypothetical situation. My doctors always want to prescribe me more Sinemet than necessary, so I have built up a large supply for the coming year(s)

healthunlocked.com/cure-par...

[Jana86]

I have also encountered PWP who have experimented with "dynamic dosing" ...trying to anticipate when they will require more dopamine and trying to fit a standard dose into what they anticipate needing. Agree completely that resilience and ability to function should increase if we can maintain a steady state in a shifting context. Again, there is a real need for research that would help us make these decisions in a more informed way...we spend millions on the search for the magic molecule that will make this nasty disease go away (with 50 years of failure) while resources to truly understand how to manage our symptoms are rarely/never available. Why? Because no one can make money from helping us have a more functional life?

[BlockRuys]

One relevant study might be the following one where they tested whether more frequent doses of lower dosaged Levodopa had an effect on the fluctuations. What they did basically was split the 100mg pills in half and took them twice. This actually had an effect where the number of motor fluctuations decreased for those that took the 50mg twice rather than one pill of 100mg. In some countries, there is Levodopa 50mg available, but in countries where this is not available, you can also just split the pill into two.

accp1.onlinelibrary.wiley.c...

"In conclusion, more frequent administration of half-tablets of the new functionally scored IR formulation safely provided more constant levodopa levels than whole tablets dosed less often. This tablet technology could facilitate the benefits of more physiologic dopamine replenishment in patients with PD, particularly those with reduced manual dexterity."

[ZebraDoodle in reply to BlockRuys]

I’m coming round to this point of view too- although by the timings suggested here you could be dissing every 45minutes!

I’ve tried the dispersible Madopar and there’s something I like that I can’t quite put my finger on. It was provided as a rescue/ pick-me-up to kick in within 15mins but the biggest benefit seems to be a more pleasant, less traumatic wearing off experience.