Sadly, I don’t think those lab results are that useful as we really want to know levels once everything has distributed into tissues as it is only at that point that you know what the effective level is. With people in the 180 lb range a single dose of 8 mg seems to have a level at 24 hrs of around 3-5. I’m sure if tested at 2 hrs it would be very high, but it needs to tissue distribute before we can really then apply the approach of using the half life to look at how long you’ll be above the therapeutic level of 3.
I’d suggest that doing a level at 18 to 24 hours post dosing and once at a dose that generates a solid therapeutic level getting a repeat 24 to 48 hours later can give an idea of what your personal half life is, then you can sort out what proportion of time you think is reasonable to be under significant mTOR inhibition and sort out your dosing interval.
This is just my approach… think it is pretty similar to Dr Green’s approach.
Anyway 2 hr levels indicate absorption, at 2 hrs and I don’t think one can make useful decisions from this.
Thanks, I’d seen that study in your “side effects” post. Those men took a liquid form of rapamycin on an empty stomach and reached their peak blood levels in under an hour. I waited 2 hours because I took it with food.
I’m 65" tall and was 155-158 lbs, and I thought I’d calculated my m2 (BSA) before, but having a hard time figuring it out now. I think it’s 1.79? If that’s right, my dose was 3.35 mg/m2 on that table, so I was in the ballpark. Still, several people in this forum who take 6 mg/wk seemed to get much lower peak serum levels.
As for side effects, when I first started a few months ago at the dose of 2-4 mg every 10 days, I developed an itchy rash on the tops of both shoulders and an itchy spot the size of a dime on my knee, which came and went. I also developed a small, inflammed bump at the edge of my upper lip on day 8 or 9, which lasted a few hours and then disappeared. Also joint pain in both shoulders and one knee in the days after taking a dose.
Since I started taking 6 mg per week just 6 weeks ago, I have no more joint pains or lip bumps. I still get the transient itchy rash on my shoulders and spot on my knee. My latest theory is that, as my sirolimus levels fluctuate, it’s causing some sort of cytokine imbalance and/or affecting my keratinocytes in such a way as to increase thymus and activation-regulated chemokine (TARC) levels and eosinophils, which are associated with sirolimus-induced rash. I did a lot of research, most of which I do not fully understand. This case report was my starting point: https://onlinelibrary.wiley.com/doi/full/10.1002/cia2.12075. From there, I found other info indicating that topical corticosteroids together with antihistimines (H1 and H2 blockers) can help. Triamcinolone did not work well for me. Antihistamines do seem to help but I’ll need to experiment more to know for sure. Hoping that my body adjusts to the rapamycin after a while and I won’t have this side effect anymore.
I think the key thing people are testing when they do the short term Cmax test is really if the medication is getting into the blood stream at reasonable levels (so they can be confident in that source/brand of rapamycin). Beyond that… yes, not a whole lot of value given the state of the science.
Absolutely, but I guess the issue is whether more is absorbed by 3 or 4 hours and redistributed. I’d suggest that a better understanding of what is going to really make up the AUC will be a level once everything is absorbed and tissue distributed.
Don’t be sad, I was just testing my absorption and any differences between the various brands. Maybe later I’ll do some testing at 2, 3 or 4 days to see what’s going on, but I’m not sure I care or what I would do differently based on the results. One change I might make is to decrease my dosage if my trough level the morning of day 7 was higher than expected, say above 1.
Bryan Johnson published his blood test results at 90 minutes and 4 days after taking 13 mg, per his “Blueprint Protocol” page. His 4-day level is below the therapeutic range at 2.5 ng/mL. I can only guess he thinks that 3 days of mTOR inhibition within the therapeutic range is enough and/or that he just wanted to verify the half-life.
I’m not sure the 2 hr level accurately addresses absorption. For example if you have version a that absorbs rapidly and let’s say you take 10 mg and 5 get absorbed in an hour but then no more vs version b that absorbs over 4 hrs but 8 mg are absorbed. The peak will be way higher on version a but the actual impact on mTOR inhibition much greater in version b. This is where a bit of a delayed test normalises this
Is there any data indicating that different versions of sirolimus which result in similar peak serum levels (after 1-2 hours) can then have signficantly varying levels of bioavailability in subsequent days, or any protocol for when the serum level does not remain at a specified level for at least X number of hours/days, in people who are doing intermittent dosing for longevity?
I haven’t heard of it, and between my husband and myself, we’re working with 3 doctors who prescribe rapamycin, including Dr. Green. None of the doctors even suggested sirolimus blood testing.
I did it on my own for three main reasons: I’m a new user of rapamycin and wanted to see my peak levels as compared to others; I wanted to know my baseline peak levels in case I make changes that might impact bioavailability in the future (such as adding back curcumin to my supplements or decreasing the sirolimus dosage and taking it with grapefruit juice, etc.); and I wanted to compare 2 India-manufactured generics (Ascend, Dr. Reddy’s) and a U.S. manufactured generic (NorthstarRx) due to articles like this one: https://wapo.st/3TmLMdf.
I may do a trough test in a few more weeks to make sure my blood levels don’t remain too high on day 6 or 7, but anything beyond that would probably not be useful.
Don’t waste your time on a trough, as it will not be useful and will be below range with standard weekly dosing.
Dr. Green reports that he tests - although I think this is when he is optimizing for people with risk of neurocognitive decline - e.g. positive ApoE4’s.
I’d suggest, having had a fair bit of education in pharmacology and pharmacokinetics, that your most useful approach is as I previously stated, look at where you are at, at 18-24 hours post dose, which will give a valid level as it will represent the drug being fully absorbed and distributed through your body, and yes, some will have been metabolized.
If you are interested in see how quickly you are metabolizing the rapamycin, you can get a repeat level in 48 hours and see how much is left, and then it is pretty straight forward to estimate your half life of the drug. Simplistically, if your level is <50% of the initial level then you will have a less than 48 hr half life, if you have >50% of the initial level then it is >48 hours. There are mathematical models to further determine this, but this is a quick approach.
Most modest single doses seem to run more in the 30’s hrs for the half life and bigger doses do seem to prolong half life - in my limited experience - I’ll get more certainty on this and better numbers over the next year as I gather more data. But that is my initial experience - but too limited to generalize.
Curious, do you know what Dr. Green’s dosing protocol and target serum sirolimus levels are for ApoE4 carriers and why?
Dr. Green says the trough level is important (https://rapamycintherapy.com/) and that at the 5 mg/wk, 20 mg/wk, or 0.5 mg/day doses of everolimus (with a shorter half life) used in the 2014 Joan Mannick study, the trough would be 0.1, 0.4, or 0.8, respectively. Mannick also said that “many of the adverse events [side effects] are related to the pre-dose [trough] concentration.”
Her study showed the most effective dose with the fewest side effects was the 5 mg/wk. Weekly dosing is what I was prescribed and what I plan to do without any further experimentation. I just want to make sure the dose I’m taking doesn’t result in a trough level exceeding around 0.5. If it did, I might want to reduce it.
I don’t think there are any dosing decisions to be made based on the serum levels after 24-48 hours and that it would be getting too far into the weeds, at least for me.
Absolutely - stick with your current plan for sure as your doctor has Rx’d it. Certainly if you are getting into big doses, you could monitor a trough or know what it will be based upon pharmacokinetics (if educated in assessing this, which you can establish through the method I mentioned - but is for a PharmD or Physician to determine).
The rationale for more dose intensity with those at risk of neurocognitive decline is theoretic and not proven — as is everything I mentioned on this post. Hopefully there will be some clarity over time. The approach in that area is often for a higher dose in goal of getting higher levels in the brain - but then due to exactly the issue you mention of not wanting an inappropriate trough before next dose often requires a longer interval between doses.
It sounds like you are on a sensible regimen - and it was really interesting to see the differences between the brands. I however think a bit longer after taking the dose would give a better comparison as depending upon the coating and formulation, some might have gotten absorbed after 2 hours - maybe not.
Dr. Green says the trough level is important (https://rapamycintherapy.com/) and that at the 5 mg/wk, 20 mg/wk, or 0.5 mg/day doses of everolimus (with a shorter half life) used in the 2014 Joan Mannick study, the trough would be 0.1, 0.4, or 0.8, respectively. Mannick also said that “many of the adverse events [side effects] are related to the pre-dose [trough] concentration.”
Her study showed the most effective dose with the fewest side effects was the 5 mg/wk (everolimus) with the associated trough level of 0.1.
I take 6 mg/week of sirolimus and tested my trough level a few weeks after starting, which was 0.6. I will do it again in a few more weeks. If it’s any higher, I may reduce my dose to 5 mg and retest again.
It is true. A greater percentage of people in the 0.5 mg daily group experienced adverse events, and they had a higher incidence of the more serious ones including mouth ulcers, which Dr. Green calls the “sine qua non” of rapalog toxicity. In her paper, Mannick also stated that “many of these adverse events are related to the pre-dose (trough) concentrations” and herself pointed out the significance of the higher rate of mouth ulcers in the 0.5 mg daily group. Also, based on the half life, the lowest trough levels are associated with the 5 mg weekly dose. From all of those things, according to doctors and researchers like Green, Attia, and Kaeberlein, the most common dosing protocol for longevity is 5-8 mg weekly.
There were more SIGNIFICANT adverse events in the 0.5 mg daily group. Consider the full picture. A greater number and percentage of people in the 0.5 mg daily group (22 or 42%) experienced adverse events than in the 5 mg weekly group (20 or 38%) and more importantly, 6 people in the daily group developed mouth sores while only 2 in the weekly group did. Aside from that, I’d just refer to my prior message.
What do you mean by SIGNFICANT ? Statistically significant or is that just your arbitrary judgement on what you consider significant ?Are mouth sores more “significant” than diarrhea ? (7.5 % with 5 weekly vs 1.9% with 0.5 daily.)
I read your post, no explanation on why you consider one regimen more efficacious than the other.
I listened to Mannick on Master One Thing podcast discussing her previous research and upcoming studies with her new rapalogs. She considers both dosing regimens equal in efficacy and only mentioned more sores with daily dosing. In fact regarding her future studies with TOR101 (similar to rapa), she stated she could go with either daily or weekly regimen. Clearly she didn’t consider the “side effects” of daily significant enough (or less efficacious) to dissuade her from using the daily dosing in future studies.
Side effects seem very individualized and also dose dependent (generally, higher the dose, the more likely side effects are). Most people report no side effects (and most people also report no obvious benefits… but slowing aging is not something I’d think most of us would notice).
I had one mouth sore at around 5mg/week, once. Never had any issues again even testing as high as 28mg in one dose.
As I said in my first response, Green and Mannick consider mouth sores to be more significant. They also the consider the trough level to be closely linked to the adverse events, and the lowest level is associated with the 5 mg weekly dose. This is why weekly dosing is now the standard for longevity.
And what I actually said was that 5 mg weekly was the most effective dose with the fewest [significant] side effects.
You are free to interpret the Mannick study any way you like.
I think the 0.5 mg daily or similar, more frequent dosing might work better for certain people, despite the higher frequency of mouth sores and the fact that a greater percentage of people in that group had side effects. But the consensus of the medical community is that, generally, weekly is best.
1.Snowbowl effect is not a part of good science.
2.Don’t confuse biohacking with medical community. The consensus of the ACTUAL medical community is NOT to prescribe rapamycin until we have convincing data from human trials, that includes Attia BTW.