LaraPo
#21
So based on those graphs, which protocol in the best?
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Who would know? The optimal is not known in humans (rats for that matter). One would choose to follow the protocol based on the reading of rapamycin studies and your interpretation of the best protocol. Personally, I like the modulation theory (pulsed dose) and from the protocols depicted on the charts, I would choose the 12mg every other week.
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LaraPo
#23
Hope somebody figures it out soon. I again changed my protocol and now take 0.5 mg every other day. In a month will break for a week or so.
As @desertshores said, we don’t know what optimum levels to target but at least the PK model allows to simulate various dosages/schedules and see what happens.
I think 0.5 every other day is probably on the low side but you won’t get high peaks which might be good.
I was using 6 to 8mg weekly but it looks like that after a few weeks the through levels only go down to 0.5ng/ml which is still somewhat high.
BTW that model uses data from a paper but everybody should do its own measurements as there is potentially a lot of individual variation.
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@约瑟夫_拉维尔 I made a model for the fasted case and here is a comparison between fasted and with fat:
The fasted has a higher blood peak but a lower bioavailability so less rapa in the organs.
Interestingly, excepted for the absorption coefficient ka), the other model parameters stay the same which is expected. The absorption coefficient ka is 25x larger for the fasted state.
The paper says that the bioavailability is 35% more with fat but this is looking at the AUC. In terms of concentration it’s 45%.
So here is the same curves but with the fasted state boosted by 45%. As you can see the only difference is the peak.
BTW this means that measuring only the peak blood level is not very useful.
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Assuming your parameter estimates and model are decent descriptions of reality then does this mean that measuring 24 hours after the dose is more robust since (a) the first derivative of the curve is lower and (b) the effect of fasted or fed is less influential at that point?
@cl-user Thanks. What does “boosted” mean? More dosage?
My purpose in taking rapa is to force autophagy to happen when otherwise due to aging autophagy is down regulated by overactive mTOR signaling. This is the theory ive bought into.
I don’t want a lot of autophagy or for long. I want to get rid of some old proteins and then stimulate my body to make new ones. In particular I want my immune system to get rearmed to do its job well.
My dosing strategy is to have the biggest impact I can tolerate that is as short as possible. I don’t want a bigger AUC. I want a smaller AUC combined with a high peak.
How do I get that?
Maybe a bigger dose fasted and with cardio exercise to get the blood flowing, and less often (1x/month)?
I tried the fasted rapa with exercise today (1.5 hours zone 2 cycling). So far I think the normal tiredness feeling from rapa is diminished. Perhaps I could tolerate a larger dose with this approach but otherwise I’m already at my maximum tolerable dose.
For me, almost all of the benefit from rapa has been from immune system improvements: body repair, allergies gone, reduced illness incidence. Maybe that’s all I can get since I’m not following the protocols used to extend the lives of mice. But no one asked the mice how they felt when under a constant and high rapa load. I’m guessing they felt like shit.
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Yes I think so. 24h looks like a good candidate to have an idea of the rapa level. Another one at 48h or later would give the clearance slope.
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The high peak is only in the blood because the gut => blood absorption is much faster than the blood => organs one but it likely has no real effect because the high rapa concentration is only seen by the blood cells.
The diffusion to the organs as well as clearance is mostly unaffected by the shape of the blood absorption peak. ie tall+narrow vs blunted+wider.
Some highly blood saturated organs, like the liver for instance, might see some of that blood peak though but not the average of the organs.
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@cl-user Thanks. This has been eye opening. I see I’ll just have to go for the benefits of convenience then. My rapa dosing day is the only day I could fast without interfering with my other health efforts.
And I don’t think concurrent aerobic exercise has any effect on the tiredness effect Rapa has on me. It was worth a try. On the other hand I felt completely normal during the exercise. Perhaps I didn’t give Rapa enough time to get into my system.
59vw
#31
Interesting kinetics. Note that paper uses an oral solution of rapamycin which may partly explain why your dosages and blood levels don’t quite correlate with what most see here. For example, as far as I know most don’t see a blood level of 17.5 ng/ml after a 6mg enteric pill dose. Just a caution that once absorbed the kinetics may be the same but extrapolating from these graphs to get a “pill” dosage won’t quite work. One would have to compare blood levels for a pill dose equivalent. I guess if you add GFJ the comparison is pretty similar (6mg oral soln seems equivalent to 6mg pill + GFJ).
Herm
#32
Right. Simple excel calculations here:
The terminal elimination rate constant ke = (ln(C1) - ln(C2) )/(T2-T1)
Half life T1/2 is simply ln(2)/ke or 0.693/ke.
C1 is the concentration at T1 hours after dosing
C2 is the concentration at T2 hours after dosing.
For example, get blood drawn around 24-36 hours and 48-72 hours post dose, and you get hours for the half-life in a personalized fashion. You should time T to the exact hour after dosing for best results.
You can then use your personal T1/2 to determine your preferred dose interval based on how long you want to be back to zero concentration before your next dose if that is of interest.
Herm
#33
Well, the absorption from gut follows Michaelis-Menten kinetics but that gets into NONMEM modeling with Vm = 4.56 (μg/l·h), and Km 13.8 mg.
Off-topic, but this is a very interesting idea—combining rapamycin (RAPA) with Zone 2 cardio. Looking forward to hearing more about your experiences and findings here.
Same here, Joseph. I think of it like this: children have strong immune systems—consider how young people generally tolerate COVID-19 much better compared to older adults. A robust immune system is indicative of overall metabolic health. Improvements in immune function could indeed be a sign of biological age reversal.
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@SilentWatcher the experiment continues to have confusing results.
Experiment
Instead of taking rapa in late afternoon for a tired feeling at sleep time, I thought I would see what happens if I took my rapa and then did a moderate dose of endurance exercise to get my heart rate up for 1.5 hours. Would that speed up the distribution to the organs? Would it shorten the time of high rapa in my body? Would it reduce the tiredness I get from rapa?
Outcome
No effect felt during exercise. I felt completely normal during a fasted, hot zone 2 ride (120-125 BPM) with some minutes at 160 BPM
The tiredness came on a hour later, right on the typical schedule. I slept well but wasn’t as tired as I would have been if taken rapa later.
I woke at my normal time feeling the rapa tiredness still with me, which is unusual. Normally it is gone when I wake even though I took it hours later.
The morning after I have zero muscle soreness. This is astonishing as I lifted very hard this week, the last time 36 hours before my rapa dose. Perhaps it will come later. I dont know what to make of it. I typically have soreness the morning of the second day even without rapa. But with rapa I am usually sore for an extra day. But now nothing.
To be continued….
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I’m seeing trough levels were at about 1.6 or so. In this study - and yes, on other medications, but no huge reason for metabolism to be different as primarily hepatic metabolism - they are going for a trough of 5-10 ng/mL, yet the daily dose was 1.2 mg/day to achieve this. The model above would have given a markedly different result than the real life result in this study as the model above would have predicted a trough of no greater than 2 ng/mL with that dose, and yet these patients were 5-10 ng/mL.
Any thoughts on that?
https://pubmed.ncbi.nlm.nih.gov/33277457/
I suspect that any model actually needs at least 2 data points for a given dose, taken in exactly the same formulation and with the identical foods (whether olive oil, nuts or GFJ), one modestly after ingestion - I like 20-24 hours, then a second a couple of days later in order to assess the individual’s T1/2 as this will vary individual to individual and will have profound impacts on trough and peak levels - especially with repetitive dosing.
The levels I’m seeing predicted from 6 mg are discrepant from what I’ve seen on lab testing.
This work is great and I’m wondering if the graph is based on an individual where you have already sorted out their absorption and redistribution the their T1/2?
I’m currently waiting for my Labcorp tests results to fit the model to my own data but in the mean time I used the measurements from that paper which used a rapamycin solution:
I would be happy to fit alternate models if people can provide me with some real measurements. Ideally I would need at least 3 points: The max then at least 2 points on the tail.
The interesting revelation, for me at least, is that the initial blood concentration peak is mostly irrelevant to the concentration of the averaged organs.
I doubt the peak helps in the model, and you’d not actually know it was the peak as absorption timing can be variable. I’ve been pretty comfortable manually looking at an individual’s absorption and T1/2 based on just 2 values - but the first value needs to be after tissue redistribution which probably 6-8 hrs would be enough, but I usually use 20-24 hrs. Then getting another level in 48 hrs allows a decent estimate of T1/2. However this model is much sophisticated in regard to the repetitive dosing, and likely being able to predict what would happen in an individual if they took their dose from 6 mg to 8 mg for example.
It would be much more practical for most people to just do 2 levels, and I doubt the peak in any way helps predict anything. Have you looked at that - as you have noted - the peak is pretty useless in my estimation.
I’m using the standard 2 compartment model (3 if we include the GI):
The central compartment is the blood+blood saturated organs and the peripheral compartment is the average of every other tissue that gets rapamycin.
I use the following differential equations and optimize the k coefficients to have fit the C1 (Blood) curve to the data.
BTW There is a better model for the rapamycin absorption in the GI (Michaelis-Menten kinetics as pointed by @Herm above) but I don’t have enough data points to fit this model.
As it’s a fully dynamic model it can simulate any dosage/schedule. We just have to get the k coefficients right. They vary with people though.
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Joseph, what is your current dosing and schedule. I’m not as scientific as the rest of the group here and am wondering if I should change my 6mg/wk dose. I typically do that for 2 months then take 1 month off. I do notice some slight edema in my right hand on this dose after about a month, so I know it’s a little high.
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