#513

A level of 6 ng/mL is immunosuppressive. Specifically, we see it used in this range to suppress organ rejection and when it goes lower than 3 ng/mL (in combination with other drugs) we start seeing organ rejection rates go up. Done as a sole drug for organ transplant

A short term study of 6 individuals for 8 weeks is unlikely to get adverse effects. So yes, someone wanting to do this for 8 weeks to potentially get these benefits - probably relatively safe. Doing this for years … I’d expect to see problems.

Here is a summary of blood levels that are actively immunosuppressing (and note it is <6 for several indications) based upon indication:

1. Kidney Transplantation (Renal Transplant)

Regimen / Scenario Time Post-Transplant Target Sirolimus Trough (ng/mL) Notes
With Calcineurin Inhibitor (CNI) (e.g., tacrolimus or cyclosporine) – “CNI + sirolimus” First 3–6 months 4–8 Most common early strategy
>6–12 months 3–7 Lower if stable
CNI-free / avoidance (sirolimus + MMF + steroids, or belatacept-based) First 3–12 months 8–14 (often 10–12) Higher exposure needed without CNI
Maintenance (>1 year) 5–12
CNI minimization or conversion (late switch from CNI to sirolimus) After conversion 8–15 Especially in chronic allograft nephropathy or malignancy risk

2. Liver Transplantation

Regimen Target Trough (ng/mL) Notes
With tacrolimus (early or minimization) 4–8 (first 3–6 mo) → 3–6 Very common in many centers
CNI-free (sirolimus-based primary) 8–12 Less common, higher toxicity risk

3. Heart Transplantation

Regimen Target Trough (ng/mL) Notes
With CNI (proliferation signal inhibitor addition) 4–10 Often added for CAV prevention or renal sparing
Everolimus more common than sirolimus in heart tx, but if sirolimus used 5–10

4. Lung Transplantation

Regimen Target Trough (ng/mL) Notes
Usually everolimus preferred; if sirolimus used with CNI 3–8 For BOS prevention or CNI minimization

5. Pancreas or Simultaneous Pancreas-Kidney (SPK)

Regimen Target Trough (ng/mL) Notes
With low-dose tacrolimus 4–8
CNI-free 8–12

6. Lymphangioleiomyomatosis (LAM)

Indication Target Sirolimus Trough (ng/mL) Reference
Pulmonary LAM (TSC-associated or sporadic) 5–15 ng/mL (most guidelines aim for 8–12 or 10–15 in practice) MILES trial (NEJM 2011), ATS/JRS guidelines 2017, and 2023 updates
Goal Reduce VEGF-D, stabilize or improve FEV1, reduce chylous effusions
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#514

Once a month I skip a weekend so 28 days on, 2 days off.

Probably don’t need to do that at this dose.

#515

28 days on, 2 days off

This is our protocol for now so we will be doing it this way until I see a compelling reason to change.

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#516

Just FYI, make sure not to do that with Rapamycin. The pills have a special coating which is needed to survive the stomach and make sure they are absorbed. (The PEARL trial kinda failed because they had much lower absorption than expected due to using some proprietary formulation rather than just using the real deal).

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#517

Tnx for the tip. Unfortunately I can’t take that advice. I’ve blood tested cyrolimous a dozen times with experiments of co-adjunivants; grapefruit extract, berberine, grape seed, peperine… (all affect same pathway +/-) and have seen mid 20’s but I have to take 12++ mg plus the adjunivants to get that high. My last test was a paultry 9 ng/dl. So I just take 2x that amount. ;( Some day we will have a target blood level from trials to know what to shoot for / not to exceed…

I’m forced to adjust rapa mg till I see decent blood values due to my personal absorption and protocol limitations. Tnx though!!! Curt

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#518

Steve, with your protocol are you measuring your trough level? Do you take into consideration daily decay factor (usually 0.707 but mine for example is 0.95). If yours is ≈ 0.707 (i.e., 70.7% remains each day) and it accumulated for 28 days and you have only a 2 day break, which means you are accumulating a lot.

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#519

According to the studies on this 1mg per day dose schedule, the accumulation level is not a big concern.

Since we have been doing this for close to 3 months now, we have not experienced any of the obvious “issues” other people have experienced with the peak and trough method. We had been doing an every 2 week x 6mg with GFJ for nearly 2 years before switching to this and neither of us had any issues with that protocol either.

study on 1mg per day rapamycin use in humans.pdf (322.2 KB)

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#520

Does it mean you don’t measure your levels and just follow the protocol in the study? The study followed that protocol only for 8 weeks. So no wonder they did not show much accumulation or immunosuppressive effects.

1mg is exactly what is prescribed to me for kidney transplant and it does accumulate which leads to immunosuppression enough to keep transplanted kidney. I track my numbers daily. When trough reaches 5 I have a break till it falls to 2.5 - 3 ng/mL and then start again to reach approximately 5.

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#521

why did you switch to 1 mg daily from the 6mg every other week w/GFJ? You would need more rapamycin on the once a day protocol. roughly 30 pills v.s 12 per month. (I do 6mg w GFJ every 21 days)

#522

8 weeks is long enough for a daily dose to reach a stable level.

FYI - Peak is high, trough is low though :slight_smile: so your trough is 2.5-3.0 and your peak is 5

And no, I don’t do any tests for Rapa levels, not very convenient here.

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#523

I’m not concerned about cost, this stuff is quite inexpensive compared to some of the other things I do.

I switched to the once daily as the studies show a couple benefits I’m interested in.

#524

This graph does not take into account individual response and clearance of Rapa at 1mg per day,

What is shows it the amount of Rapa as affected by the half life, not the serum level

It shows the theoretical static peak reached in about 20 days or 3 weeks with a mid level half life of 67 hours. And the trough with the 2 day off.

The graph is for 28 days on and 2 days off with a restart on day 31

Rapa_1mg_28-on-2-off
Rapa_1mg_28-on-2-off1833×916 130 KB

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#525

ahh, ok. I was just wondering because of the recent tariff issues/cost.

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#526

I’m Canadian, not a problem for us :slight_smile:

#527

@Steve_Combi You can get india medication send to Canada no problem?

#528

My peak is 4.13 and trough 3.2. And I don’t want to go higher on any of them.

#529

Thanks so much for all the detailed stats info Dr. Fraser !

#530

Thanks so much for all the detailed stats info on this matter Steve !

#531

Yes, there is a personal use exemption for up to a 90 supply.

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#532

One of the latest research posts has the subjects taking 1 mg for 4 months and no immunosuppressive effects. See below excepts:

Rapamycin exerts its geroprotective effects in the ageing human immune system by enhancing resilience against DNA damage

Low-dose rapamycin reduces markers of senescence and DNA damage in humans in vivo

Taken together, our data so far show that age-related immune subsets exhibit features of DNA damage, cell senescence, and mTOR hyperactivation, and that human ageing is accompanied by increased mTOR activity across all immune cell types (Figure 7d-e). We have further demonstrated that treatment with low-dose mTOR inhibitors improve survival and reduce markers of senescence and DNA damage in human T cells treated with a genotoxic agent outside of the body. Such findings are important but require in vivo data before they support further clinical action. We therefore assessed whether rapamycin treatment impacts on immune cell DNA damage and senescence in vivo in humans, analysing PBMCs from participants of a single-blind, placebo-controlled trial (NCT05414292), in which older male volunteers received either 1 mg/day rapamycin (n=4) or placebo (n=5) for 4 months (Figure 8a). While the primary endpoint was to assess changes in muscle mass and protein synthesis, we aimed to assess features of immunosenescence in PBMCs isolated at several timepoints throughout the trial.

After 8 weeks of intervention, the concentration of rapamycin in the blood reached an average of 3.24 ± 1.81 nM in the treatment group (Figure S5a), i.e., within the same order of magnitude as the doses used in our in vitro experiments (10 nM). To address concerns of immunosuppression by rapamycin, the white blood cell count was assessed at 8 weeks; there were no significant differences in leukocyte counts in the blood over the initial 8-week rapamycin treatment period, and between rapamycin treated and placebo controls, suggesting that this low-dose rapamycin treatment regimen was not immunosuppressive (Figure S5b).

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