That seems an oversimplistic way to do a dose-conversion: they were just measuring how much drug it took to get the same trough blood concentration of either drug. But each drug has different pharmacokiinetics beyond the trough concentration, and also different pharmacodynamics (e.g., differences in mTORC1 vs. mTORC2 inhibition at a given concentration and a given time of exposure) and tissue selectivity (e.g. everolimus has greater access to the brain). So just saying how much of either drug you have to take to get steady-state 12-15ng/mL of each is not likely very meaningful.
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Agreed. As the “Everolimus and Sirolimus in Transplantation-Related but Different” paper from 2015 said:
Although binding of everolimus to FKBP-12 is approximately 3-fold weaker than that of sirolimus [19], everolimus blood trough concentrations targeted in transplant patients are typically lower than for sirolimus (3–8 ng/mL versus 4–20 ng/mL [24–26]).
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According to Joan Mannick (25:31), everolimus is equivalent to rapamycin.
And that you actually can take a lower dose of everolimus to get the same treatment effect as rapamycin. Meaning you get higher levels at the same dosage.
@RapAdmin what if people have taken twice the dosage of everolimus thinking it’s half as effective but it is actually more potent 
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Everolimus seems to be used as a cancer drug rather than for immunosuppression and for organ transplants. Rapamycin doesn’t seem to be used for that, at least much. It can stop the growth of certain cancers.
Brand name Afinitor.
I’m thinking another positive with everolimus, is that the scientists behind it spent a lot of money, effort, and time, to create a rapamycin alternative. That process might’ve been intended to make a better alternative, and thus there is the chance they’ve succeeded.
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I would think that the uncertainty with Everolimus is greater than Rapamycin.
Why do you think that? Everolimus has been used in the only clinical trial to show weekly dosing being safe / improving aging (possibly reversing immunosenescence)? It was developed in the 90’s, a looot of clinical trials has used it.
Well… there have been many dozens of lifespan tests done with rapamycin, and few if any with everolimus. So just from that data, we have more confidence that it produces favorable longevity results.
I tend to think that the molecule is so close to rapamycin that effective differences in results will be minimal. But - we don’t know for certain until testing is done. But - given the opinion of Richard Miller and other experts who don’t think its worth even testing everolimus for longevity (because they feel its likely to be identical (or very close) results to rapamycin and thus wasted time and money - I tend to go with the opinions of the experts.
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I think there is a lots more data on Rapamycin. In some senses once a lot of people are taking something if it causes any problems then we are more likely to know.
However, I have not tried to do a complete summary of who has taken what.
Good morning, questions for the this great group of very intelligent people. I have a very small 6 pound 12 year dog… he is currently on the smallest dose of Rapamycin .5 mg available Dr Kevin has me dosing 1x per week because of his weight. He is doing well at this dose but I really haven’t seen many benefits. I was hoping to dose more frequently so was looking into Everolimus. Which is available in .25mg I understand that that is less of a dose than .25 rapa would be. I also remember reading that unlike Rapa the Everolimus an be split?
What would you do if this was your baby? Leave him on the once per week Rapa? Switch to Everolimus dose more often? The .5 Everolimus is cheaper if I buy and split.
Suggestions please
I’m assuming you are treating for longevity and not cardiomyopathy. Since we really have minimal longevity data in dogs on rapamycin, I’d try to mimic Kaeberlein’s TRIAD trial and dose at 0.15 mg / kg (2.2 lbs/kg so 6 pounds = ~2.7 kg). Your dog’s dose would be 0.4 mg so the 0.5 mg dose he is getting is close enough. I’m not sure what benefits you are looking for as the effect will be to slow the aging process and the benefit will be slower aging and prolonged health rather than a dramatic reinstatement of youthfulness. At this point that’s probably the best you can do as there is some evidence that too high a dose can cause toxicity. More isn’t always better. Wait for the results of the TRIAD trial and adjust at that point if there is reason to.
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I wanted to soften the blow here with some details from the paper. They injected Sprague‑Dawley rats daily with 2, 4 and 6 mg/kg of rapamycin for four weeks. First, intraperitoneal injection has a much larger effect than the same dose taken orally. See, for example:
Second, daily injection would result in significantly higher levels of everolimus.
Third, for a 0.200 kg Sprague‑Dawley rat, rough allometric scaling to a human dose looks like this:
- 2 mg/kg = 0.4 mg ≈ 34 mg @ 75 kg
- 4 mg/kg = 0.8 mg ≈ 68 mg @ 75 kg
- 6 mg/kg = 1.2 mg ≈ 102 mg @ 75 kg
My takeaway: you would need to consume extremely large doses of oral everolimus every day (or two) for weeks to match the experimental design of this study. Since the rats in the 2 mg/kg group regained the usual number of sperm after a 24 week recovery, I suspect the long-term consequences of lower and intermittent dosing are minimal.
That being said, a 2015 paper from the Lamming lab showed reduced testicular weight from both the 1x/daily and 1x/5-day dosage schedules.
Still—my read on the literature so far suggests that these changes are temporary and revert to baseline after ceasing rapamycin (or everolimus in this case).
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Good post. We also cover this risk and the papers related to it in these posts:
Possible Risks to Humans: Possible Rapamycin Risks for Healthy Humans (Part 2)
Here: Starting rapamycin next month - 27 years old - #4 by RapAdmin
Hi guys.
I’m new here and in this Rapamycin’s world.
I would like to start with Rapa but here in Brazil, i guess it is kind of impossible to get that without prescription. So I have a transplanted cousin that has Everolimus and he can give me some. So my question is can I take Evero instead of Rapa? Is that the same? I guess its better to use a Evero from i reliable source than order Siro from India. What do u guys think about it?
p.s: sorry for my bad english
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Sirolimus from india is good quality so there is no difference.
And there isn’t really any difference between everolimus and rapamycin.
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Generally, rapamycin and everolimus from India seems acceptable in quality based on these types of lab tests we’ve seen: Rapamycin / Sirolimus from India, Lab Test Report on Quality / Purity
But - I’m personally not a fan of small Indian Pharma companies because in my opinion it seems that they are more likely to be selling a lower quality product. See this post: Overseas vs obtaining a prescription - #8 by RapAdmin
Also - perhaps of interest: Side Effect Profile for Everolimus: Doses from 10mg to 70mg per Week
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This is not a good paper to draw that inference. As far as I can see, they put rapa directly into the drinking or gavage water with no additional formulants. As is pretty well known, oral rapa has to be protected from stomach acid or it will be degraded before it gets into the small intestine and absorb: trying to get this right was what held up the ITP study, and the ITP, Trivium Vet (for the TRIAD study), and others use various kinds of microencapsulation to ensure delivery intact to the lower GI. Since they here just put it in the water, the absorption will be far lower and the dose is therefore not comparable the same way it would be.
Significantly higher than what?
As above, you would need to somehow adjust the starting dose lower to account for the reduced bioavailability of the straight-up rapa in water get an equivalent dose in pharmaceutically-formulated rapa tablets.
Your point is well taken, but not applicable in this instance. Per the paper, the oral “gavage group received 1.5 mg/kg rapamune”. That’s the nanoparticle-based pharmaceutical formulation you reference at the end of your post.
The daily intraperitoneal injections used in the study @hunterama1 mentioned (Liu et al. 2017) would result in significantly higher levels of everolimus than the 3 times a week every other week intraperitoneal injections of rapamycin used in the study I had just mentioned for comparison (Leontieva et al. 2014). It’s the difference between 14 injections and 3 in a two week period.
I referenced that Blagosklonny paper because it directly compares the same dose of rapamycin given intraperitoneally and orally. But, the different pharmacokinetics of intraperitoneal injections and oral intake are widely known within fields that work with rodents. Most drugs injected i.p. absorb rapidly because the peritoneal membrane has a large surface area and a rich blood supply. So, i.p. injections typically result in higher bioavailability and a faster onset of action compared to the oral route. Drugs injected i.p. typically clear faster, too.
Here’s Matt Kaeberlein on the topic:
Analysis of rapamycin levels in blood suggests that daily i.p. injection of 8 mg/kg yields blood levels of around 1800 ng/mL one hour after injection and 45 ng/mL 24 h after injection (Johnson et al., 2013c). For comparison, blood levels of 3–4 ng/mL rapamycin were measured following dietary delivery at 14 ppm in the same mouse strain (Zhang et al., 2014) and studies from the ITP have reported between 9–16 ng/mL at this dose and 23–80 ng/mL in animals receiving the 42 ppm rapamycin diet (Miller et al., 2011). Thus, daily i.p. injection of 8 mg/kg rapamycin, which appears to be well tolerated in wild type mice (Johnson et al., 2013c), yields circulating levels of the drug that are at least 20-fold higher than the highest concentration that has been carefully tested for effects on normative ageing. (Kaeberlein 2014)
Here’s a helpful figure from (Johnson et al. 2015):
And, to get a better sense of the comparative doses, here’s the math for the highest oral dose:
378 PPM = 378 mg/kg of food = 0.378 mg/g × 4 g average mouse food consumption = 1.512 mg / 0.025 kg average mouse body weight = 60.48 mg/kg body weight.
Approximately 60 mg/kg body weight of encapsulated rapamycin (the same formulation used by the ITP) yielded 709.8 ng/mL, while 8 mg/kg body weight of i.p. injected rapamycin yielded 1842.0 ng/mL.
I hope that clears things up.
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It’s now late October 2023. This study was published 4 days ago. Please, may a smart person read this study and explain what it means. The standout quote is “ The analysis revealed that the cellular response to everolimus differs dramatically from that of rapamycin and temsirolimus.“
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"Everolimus affects the ubiquitin-proteasome system (UPS) more than sirolimus. This increased effect on the UPS can be considered both good and bad: The good: - Everolimus’ greater impact on the UPS enhances its anti-tumor activity compared to sirolimus. It causes more degradation of proteins involved in cell proliferation and survival. The bad: - Excessive inhibition of the UPS by everolimus can lead to toxic accumulation of proteins in cells. It may also cause more side effects than sirolimus. So the increased effect of everolimus on the UPS has tradeoffs. It improves anti-cancer efficacy but also likely worsens tolerability and side effects.
“Determining if its overall impact is good or bad depends on the clinical context and individual patient factors.”
The normal dosing of everolimus is 10 mg/daily for therapeutic effects on cancer etc.
I would think that a once weekly or even every few days of dosing everolimus wouldn’t have any toxic accumulation of proteins in cells. I know nothing about medicine, so I don’t know, I can only surmise from the literature that I have read.
The aging brain shrinks in old age. Nothing is currently known to stop this. Maybe we can slow it down a little. After my current supply of sirolimus runs out I am going to try everolimus because it can cross the BBB and my old brain can use all of the help it can get.
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Perhaps you found this but here is some information on Sirolimus and Everolimus ability to cross the BBB in mice. It appears both do it poorly but Everolimus about 2x as well as Sirolimus.
BlockquoteRapamycin and everolimus only poorly penetrated into the brain
(brain:plasma ratio 0.0057 for rapamycin and 0.016 for everolimus
https://www.sciencedirect.com/science/article/abs/pii/S0028390818304684?via%3Dihub
I’m not aware of human data.
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