#41

Pharmacokinetics and Safety of Single Oral Doses of Sirolimus (Rapamycin) in Healthy Male Volunteers
Therapeutic Drug Monitoring
22:537–544 © 2000 Lippincott Williams & Wilkins, Inc., Philadelphia

“After single oral sirolimus doses of 0.3 to 8 mg/m2, absorption was rapid and peak blood sirolimus concentrations occurred within 1 hour in all volunteers.”

I chose 90 minutes to give my patients leeway. They can go to the lab 45-60 minutes after ingestion. By the time the lab actually draws the blood they are all within the 90 minute range.

Blood is drawn at my office by my staff or at a LabCorp draw station. I have had no problem with insurance coverage for the test. The therapeutic parameters are provided by the lab. I believe that by knowing the peak level I can provide the widest margin of safety.

The use of sirolimus in Longevity Medicine is a long game. I monitor a variety of physiognomic, physiologic, psychologic and biochemical parameters at 6 month intervals. Participants work with our Nutritional Counselors and Exercise Trainers as part of the program. I do not think it is reasonable to use sirolimus/rapamycin in a vacuum.

It might be reasonable to obtain a second level in 72 hours. I would appreciate advise

Warren M. Ross, MD
Integrative Medicine at Crossroads/Longevity Program
410-997-5191

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#42

@DeStrider, as a devils advocate response I would suggest that the first principle is a quote from the 2016 Nobel prize speech from Ohsumi:
“Life is an equilibrium state between protein synthesis and protein degradation”. Therefore the principle that you suggest that more Rapamycin is better (‘we should err on the side of too much’) is not sensible from a principle point of view, even before you consider the side effects of such an approach.

In addition, human studies show benefit from rapalogues with short bursts of low dose: (Mannick showed that the immune system can be boosted in 12 weeks, Wen showed that rheumatoid arthritis can be improved within 6 months). This doesn’t mean that high-dose long-term rapalogues might be useful, but there is no data as far as i am aware to support this.

However, if modern life is plagued by us living in an ‘mTOR hyperactive state’ then I agree that we should be down-regulating mTOR more than we are up-regulating it. But this is still in a balance of episodes of down-regulation and episodes of up-regulating.
Personally I like the @John_Hemmingway approach of 6mg rapamycin plus an accelerator (in his case, pomegranate), with gaps in between (where I am lifting heavy and eating high protein).

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#43

Yes, 6-7 mg + an accelerator like grapefruit juice is what I am thinking of. Today I took 6 mg + GFJ. I think the only difference between my and @John_Hemming approach is the time between doses. He takes it every 3 weeks or longer while I prefer a gap of only 1-2 weeks.

Once you go above 20 mg equivalent, you run the risk of MTOR rebound. Unfortunately we don’t have any information on the space between 20 mg and 40 mg in relation to MTOR rebound.

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#44

I think folks who take this advice may be losing the plot.

The object of this game isn’t “optimization”.

We presently don’t know what dose is the right dose. You can’t optimize when you have no way to measure the success or failure of your dosing regiment.

The goal at this time is to “bridge” between today (when there are many unknowns) and the future (when we’ll know more).

When studies, like the Dog Aging Project, produce results we’ll know more.

In the meantime, I believe the dosing should be conservative. Think of it as a Goldielocks zone between Zero Risk (0 mg) and High Risk (symptoms).

I’m taking 1 mg for every 30 lbs of body weight. I’ve only had mouth sores once.

I take a month and a half long break every 4 and a half months, so I run 2 cycles per year.

I may not be taking enough to get the best results, but I’m hoping not to screw my body up while we wait for more information.

Thankfully, studies are being done and the results will come soon. There’s no need to panic and do potential damage to your body.

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#45

I’d disagree. The goal is to optimize. Unfortunately, you’re correct that we don’t currently have the tools to do that.

Why is it you take a break from Rapa?

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#46

Does anyone know when we might see the initial readouts of this?

Or is the rapa leg at complete risks because of the NIH funding not being renewed ?

#47

Matt K. used to say 2026, but that was before funding was pulled. I don’t know now, and I don’t know if anyone knows.

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#48

While our cells do get replaced on a regular basis, each cell type has it’s own time frame for replacement.

Neutrophils can be as short as 4 hours up to 8 hrs

about 120 days days for red blood cells

10 to 25 years for bone cells

And a wide variance throughout cell types of which there are over 200 known.

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#49

You can’t optimize dosage when you don’t have a frame of referrence. Until there are studies related to dosage, you’re just guessing.

When we know more, hopefully we’ll be able to optimize.

I take a 6 week break every 4.5 months, because long term Rapamycin useage is known to down-regulate MTor2 and that’s not a good thing. By taking a break, I am attempting to mitigate the effect on MTor2 while having an effect in MTor1.

I also think it’s wise to cycle off the medication, in case there are other unknown negative side effects.

Since there have been no long term studies of the safety of Rapamycin administered to otherwise healthy people, it makes sense to hedge your bet.

I suspect many of the early adopters of Rapamycin are the sorts of people who tend to lean into whatever they do. This isn’t a thing most people do. So it stands to reason that we’d have a lot of gung ho personalities in this group who would be pursuaded my a “more is better” phylosophy.

But the goal here is to thread the needle between taking action to extend life, without doing youreslf harm.

Abscent more information, the “unknown unknowns” are something you should be worried about.

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#50

I don’t think there is evidence to support either of these.

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#51

I suggest you Google Rapamycin MTor2

The impact on MTor2 is well documented.

#52

We do know that doses below 20 mg equivalent we don’t see MTOR rebound in humans. At 40 mg, 50% of people had MTOR rebound. So the magic number for MTOR rebound is between 20-40 mg. That’s why I recommend not going above 20 mg or 6 mg + GFJ.

We’ve had people take a 500 mg equivalent dose (100 mg + Ketaconazole) and they turned out fine. So we know you can’t OD. Also, look at the marmoset colonies. They did just fine on a higher dose.

Rapamycin, IMHO, is incredibly safe but not perfect. You can die from a bacterial infection which is probably the worst case. Other side effects can be controlled with other medications (hyperglycemia and hyperlipidemia).

And to be honest, my “high dose” is not actually that high and I am willing to put up with apthous ulcers, slow wound healing, and diarrhea in exchange for a healthier and longer life.

Of course if additional information comes out, that will alter my course of action just as this marmoset data has.

The marmoset data is probably the best data we are going to get for a long time. Human studies will be too short term to be conclusive and there are no other long term studies in the pipeline. Waiting for more data is like waiting for Godot at this point.

The data is in. It’s time to make a decision on what we have. It’s neither perfect nor guaranteed, but it’s enough for me.

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#53

Really?? 100mg of rapamycin pills…that’s a lot of pills!! And a CYP3A4 inhibitor?? Were they suicidal? Are you sure that it didn’t cause brain damage? Was it @SNK ?

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#54

May I ask what this is based on, Chris?

#55

Please see these excellent posts by @McAlister on dosing. As always, I welcome other people’s opinions. We need to work together to find the best possible outcome.

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#56

Thanks Chris / @DeStrider .

  1. I read read the first post and while it very helpful to understand rebound risks and layers out the case that <20mg equivalent rapa ranges may not lead to rebound dynamics, I’m not sure I follow how that answers the question about risks of decreasing mTORC2 from taking rapa in the first place?

It seems that rebound is about mTOR and mTORC1 (and perhaps mTORC2) going UP - but what we are worried about with regards tk mTORC2 is it being inhibited and hence going down.

What am I missing? Please do help me understand if in incorrectly understanding things here.

  1. I also read the second post and it was also a good, valuable read. However the take away there seems to be that the lower range to target is not 20mg but might be much lower than that.

The post concludes

Personally, a 12 mg dose of rapamycin taken with food yielded an approximate peak of 17.9 ng/mL three hours later. The blood level (ng/mL) achieved by a given dose (mg) varies widely from person to person, so everyone needs to get their own blood work done.

Takeaways

  • Unless human clinical data eventually says otherwise, design your dosing schedule to avoid inhibiting mTORC2. You’ll need some personal data points to assist with that. A peak rapamycin level of 10 ng/mL probably avoids inhibiting mTORC2.*

Where as you can see he is saying from at least his own data that 12mg yields at least a 17 ng/mL peak which is above the 10 ng/mL peak to be “safe from mTORC2 effects” and hence 12mg is too high so 20mg is not a “safe limit” for mTORC2 (even if it perhaps is “safe” for avoidance of mTORC1 rebound).

Please let me know if I misunderstood anything above or in some other ways am getting something wrong here also.

In that second link you posted @McAlister also says

Based on rapamycin’s half-life, I expect most people to have detectable levels at 7 days. I suspect that matters less for lower doses, as the ng/mL amount of rapamycin would likely be below the mTORC2 inhibition threshold. But for higher doses, 14 days is probably wiser. But personal blood work is necessary to determine those parameters.

Given that first bolded part people who do weekly rapa - without breaks - might over the course of weeks keep slowly building up higher and higher doses in their system.

(The second bolded part on doing 14 day cycles might help solve that issue)

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#57

I was looking at this part:

What do we know about when rapamycin begins affecting mTORC2?

In male and female C57BL/6 mice, 16 weeks of oral rapamycin (2.24 mg/kg body weight/day ≈ 22.7 mg at 75 kg body weight) had no effect on the phosphorylation of Akt (Ser473) and PKCα (Ser657)—both targets of mTORC2—but decreased the phosphorylation of p70S6K (an mTORC1 target) by ~34% in whole brain lysates (Halloran et al. 2012) 1. This indicates that, at least in the brain, concerns over rapamycin’s capacity to suppress of mTORC2 are not warranted.

16 weeks of daily high dose Rapamycin did not affect MTOR2. That’s why I also included the mouse measurements.

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#58

Ok, I see that subpart, but @McAlister does not seem to use it the way you are doing, he is sharing it as one data point that he then puts in context with mice data on lower levels leading to mTORC2 inhibition

and (if I understand it correctly, perhaps not as this is not my area of expertise) he also explains that one cannot only look at the direct mTORC2 lowering pathway (that the section from the one mouse study you decided to point to), but also that if mTOR / mTORC1 overall is lowered, then mTORC2 can be lowered through that in an indirect way

In 26-week-old male psPten–/– mice (n = 15), eight weeks of 3x weekly oral doses of a highly bioavailable nanoformulation of rapamycin called Rapatar appeared to increase the amount of phosphorylated Akt at both a low (~0.1 mg/kg rapamycin) and a high (~0.5 mg/kg rapamycin) dose, but only the high dose was significant (p = 0.02) (Antoch et al. 2020). The increase in pAkt could result from releasing mTORC1’s inhibition of IRS1/2 and mTORC2 (Rozengurt et al. 2014). Direct inhibition of mTORC2 has previously required higher doses: e.g. 10 mg/kg in (Halloran et al. 2012) and 8 mg/kg in (Schreiber et al. 2015). These results indicate that rapamycin causes a compensatory activation of Akt at doses below the threshold of mTORC2 inhibition.

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#59

Any comment on what I wrote in (1) above?

And on how to weigh (2) above in the context of thinking of threshold for mTORC2 risks starting to be relevant?

#60

Getting into the finer details of dosing is going to vary a lot due to individual differences. For instance, the 6 mg + GFJ I plan take as a 95 kg male will probably be equivalent to a 4-5 mg + GFJ dose that a smaller 75 kg person would. Therefore my dose and @desertshores dose will probably yield the same blood concentration due to our size difference. For most people here, a high dose would probably fit in the 4-6 mg + GFJ range.

I also am taking into account anecdotal evidence from Bryan Johnson as he is constantly monitored by his medical team and if something is going off the rails, he’d be able to detect it and change. He takes the equivalent of a 4 mg + GFJ dose. And of course we have the amazing @Agetron and @desertshores who have taken and are currently taking relatively similar doses.

Based on my research and experience gained from this board and looking at my own lab work, I feel confident in my current higher dosing schedule of 6 mg + GFJ every two weeks. I am thinking of taking an extra dose of 3 mg + GFJ the second week.

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