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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@Brimstone Heres what I do. The edema thing is something I experienced from a higher rapa dose and with experiments with a lot of citrate (sodium / calcium / magnesium/ potassium). I’ve given up both.
I weight 200 lbs
- if I am sick or feel something coming, I skip my dose
- if I have an infection (boil, etc), I skip a dose
- if I am feeling beat down for any reason, I skip a dose
- I take Rapa every 14 days, and after 28 days I take an extra 7 days off (using this approach I do not get infections and almost never get sick)
- 4mg rapa plus gfj (3 grapefruit: ~10-12 hours before / 6 hours before / 2 hours before l)
- no food beside gfj for 12 hours before and after (this is for body fat control. I also hope for a higher peak and lower AUC for rapa but I’m told this doesn’t happen)
- I skip all my meds and supplements for the rapa day and day after. I add metformin ER for the 24 hours before and after my rapa dose
- I stop weight lifting for 36 hours before rapa (to recover), and then avoid lifting for at least 24 hours after depending on soreness. I ride my bike for an hour a day on these days.
- I eat low protein for 24 hours before rapa, and for 24 hours after rapa. This is especially true during the GF fast.
- I was taking Rapa in late afternoon to get tired before bed, and then sleep it off. That works well. I just started doing a moderate intensity 1.5 hour bike ride starting an hour after taking Rapa. So far the result has been no muscle soreness and no fatigue at all on the second day. I like this better so I’m switching to this.
Hope that helps. You should know that I am not a doctor and I essentially have no idea what I’m doing with rapa. As far as I can tell, no one can tell anyone else what will work until they try it and see what happens. Be conservative. Take your time. Don’t get emotionally attached. “Mind like water” (from a podcast I’m publishing tomorrow).
Good luck
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Herm
#42
One of the things to watch out for in structural mathematical modeling is trying to estimate too many parameters with too few data points. In this case, you are trying to estimate 5 parameters, so you would need a set of time points along the PK curve such as these authors used for sirolumus: Blood samples were collected onto sodium edetate for determination of sirolimus in plasma and whole blood, before administration and at 0.33, 0.66, 1, 2, 3, 4, 6, 8, 12, 16, 24, 48, 72, 96, 120, 144, and 312 hours after administration of sirolimus or placebo. (Brattstrom C et al Therapeutic Drug Monitoring 22:537–544; 2000) They employed Non-compartmental analysis, which makes fewer assumptions than a compartmental analysis. With enough time points, the parameters resulting in best model fit are determined by the model run minimizing the error or difference if you will between the predicted and observed time points.
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Looks like the high fat version slows down the peak so that there is enough point to fit a Michaelis-Menten model. I use a non linear optimizer to find the k coefficients giving the best fit and it works quite well.
Here is the latest fit:
Zoomed on the peak:
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[Disclaimer for those who skipped the discussion above, The data for this model comes from a paper and obviously individuals will have variations in term of absorption, distribution and clearance compared to that]
Comparing 1x 6mg vs 2x 3mg, 3x 2mg or 6x 1mg spaced 24h:
Here is the distribution to the average organs:
I would say it’s probably better to stay on a 1x 6mg schedule unless people want to avoid an initial higher peak.
BTW the other ones are still high after 1 week.
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Very helpful thanks. Just to clarify, you take 4 mg of Rapa every 14 days? Then after 28 days you take 7 extra days? So, it’s 2 doses in 35 days? I just was to make sure I’m reading it right.
My current methodology is 6 mg weekly for 2 months, then I take a month off. I take 100 mg acarbose with every meal and take 100 mg canagliflozin daily. To your point, I have no idea if this is effective or not, but I can tell you that my blood tests are typically very good on all parameters. Like you, I rarely, if ever, get sick. The only difference I see is that Rapa gives me an almost euphoric like high and gives me energy. I have to take it in the morning because at night it would make sleep impossible.
And, I completely understand that we are all winging it and that you aren’t a doctor, but I appreciate that disclaimer. LOL.
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Yes, that is correct but it’s 4mg with gfj. Call it 12mg. We are all winging it. I am very cautious about getting addicted to it and being reluctant to miss a dose. I’ll skip a dose for many reasons. I have tried higher doses and more frequent doses. This pattern feels the best to me.
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I’ve never experienced anything like that, I gotta microdose some golden teacher to get that 
