The small sample size certainly produced some inconsistent results, especially with the grapefruit juice group.
Also, remember the grapefruit juice used in those studies was a special GF juice provided by the state of Florida researchers that specifically had high levels of the active ingredients that maximally inhibit CYP3A4. We have no idea how much of those active compounds are in standard store-bought GF juice and/or how much they vary from batch to batch, seasonally and/or between brands.
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Most all of the pharmacokinetic studies I’ve read showed significant inter-person variability. Our individual n=1 responses are very complex, leading to intrinsic and fundamental differences in absorption between us, not explained in study replicability/reproducibility.
There are polymorphisms in the intestinal and liver enzymes, including CYP3A4, and others (CYP3A5, CYP2C8, and CYP2C19). There are polymorphisms in the mTOR genes! We all have different gastro/intestinal functionality.
Therefore, if we’re trying to reach certain Cmax/AUC/trough targets, we need to each do our own pharmacokinetic experimentation.
You could take an alternate, blast away approach, starting with high dose, and then dialing back when you reach discomfort/toxicity thresholds. Based on previous studies, these DLT (dose limiting toxicities) markers are noticeable, measurable & reversible.
Here are just a few references of polymorphism effects on pharmacokinetics.
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Let’s not forget the variability in the Sirolimus in the pills you get. Since that is the first number in all these calculations it has a profound effect on all the number crunching that follows. Given the host of generic sources and the know problems in quality/quantity, a 1 mg pill could be 1 mg or maybe 0.5…or maybe 0.0.
Testing is expensive but could we set up a system where we join to have a system to share cost of testing across a variety of “preferred” vendors who we use and have good service and price. Publish that. Then do this again in 2 months (or on some continuing basis) so we have validated vendors. Not simple but given all the effort in trying to get to the best dose and other costs involved it seems worthwhile. That is my biggest question in rapamycin dosing…what’s in the pill.
Or maybe MK could share his testing results and the vendor and we can use that.
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You are not questioning the quality of the Sirolimus in these clinical studies? They are using Pharma grade product, so this is NOT a variable in theses studies. So the inter-person variability is fact beyond the drug.
Now I do agree with you that for those of us sourcing generic product from all over the world, then yes, this adds yet another variable. You’d have to have to analyze every batch you receive, and even then, what is the variability/purity within the sample.
Not questioning the quality of the message used in the studies. That is not the point. The point is the quality of the product we buy for our use. Was just a thought in case they did buy from some traditional vendors. Someone on here wrote that was the plan for the big dog study. IDK. Doesn’t hurt to ask…it is in KB and other Rapa boosters interest to help get good, potent product into the market.
As for testing the generics we buy from India, there are 4-5 main sources. Yes I do realize there are 100’s of sellers but easy to narrow down to a few…one who have a reputation with people here. Thats a detail to be worked out and can be done. And they have a brand or two each. So with pooled resources testing 10 samples is not that big a deal. True, one batch could be fine and a month later not good…but you have to start someplace. I’d sure rather buy a tested "good’ brand to start then one with poor content. And follow up testing over several months establishes the vendors with consistently good product.
Intrabatch variability is possible but much less a concern than very low quantity in entire batches…that would be a manufacturing defect not just cutting the amount of product in everything. So you deal with the worst problem first.
And maybe we find its all up to snuff. So one variable sorted out.
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I’ll ask about sirolimus blood levels at the next AMA in May.
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Yes got the email today.
Looking forward to it.
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I looked at this data and had my 10mg BioCon (there’s something about this brand name that makes me uneasy!) sirolimus blood level tested 1 hour after dosing by LabCor. I was expecting around 47ng/ml based on the above paper but only had 14.7. I also had 1/2 grapefruit for breakfast so very low level. I thought maybe I’d missed the peak so I tested a second time about 2.5days later reasoning that if it was the peak, after roughly one half life I’d have 7.5ng/ml or higher if I missed the peak. The result was only 2.7ng/ml. From these data it appears I have some very potent CYP3A4 enzymes because very little made it into the blood and what did appears to have been degraded far more quickly than the reported 1/2 life range. I wonder how variable and long lasting the actual amount of rapamycin in the blood is amongst individuals and I would certainly encourage people to have a least two tests done. One 60 min after dosing and a second test roughly 60 hours later. You might not have what you think you have!
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Welcome to the forum and thanks for posting! Yes, its funny, “BioCon” isn’t a name that gives you a lot of confidence in the product is it? One of those names that they warn you about in marketing classes that likely means different things in different cultures… and obviously doesn’t translate well from India.
Thanks for sharing your blood sirolimus level results and dosing, its really interesting to see these results for people.
The research does suggest that there is a high level of inter-person pharmacokinetics with regard to rapamycin. I was just posting this entry into another thread on mTORC1 and mTORC2 inhibition - but its equally relevant here:
I’ve not done extensive research on this, but this paper on doses for kidney transplant patients suggests:
The usual maintenance dose of Sirolimus in these patients is 2 to 5 mg/d and its optimal maintenance trough level is 5 to 10 ng/mL. The required Sirolimus doses may differ markedly from patient to patient. It is because of high inter and intrapatient variability in its pharmacokinetics.
I think everyone here is still trying to figure out the exact value that of the blood sirolimus level testing… I mean its interesting, but I’m not sure of any actionable value to the information. We don’t have any target blood levels (for example, that would optimize longevity), we don’t have any target AUC for the week, etc… and there is a lot of inter-person variability - so what works for one person may or may not be relevant to another person.
From your experience - it wasn’t clear how long before you took the rapamycin that you had the 1/2 a grapefruit… It seems from what I’ve read that grapefruit juice peaks in terms of its CYP3A4 inhibition between 1 and 2 hours after consumption. Were you in that range? How long have you been doing this protocol? (10mg with 1/2 grapefruit) - and have you had any side effects?
While I am very interested in knowing my peak blood sirolimus level, and daily blood sirolimus level over the days after initial dosing so that I can perhaps figure out my AUC (area under the curve), or total exposure to the drug - I also don’t expect this to really be of value until the human clinical trials work is done that tells us what we might want to target for optimal results. Or, perhaps if we all share our blood sirolimus levels and regular blood test results, we may be able to get an idea of the dose response relationship between the rapamycin and different variables in our blood tests that we consistently see (so more people tracking and sharing these two pieces of information would be good).
I think the key value that we do know (or at least think we might know) right now is that we was to get a low trough level (lowest level of blood sirolimus level) before the next dose, so as to minimize risk of mTORC2 inhibition - and we want to get that down to the 1ng/ml level or below (roughly). So in my case, for this I would want to take the blood sirolimus level at day 7 after taking the rapamycin, to see my blood levels just before I take my next dose of rapamycin the next day.
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Biocon claims to be India’s largest biopharmaceutical company with 13,500+ employees. They serve 120 countries. They have been around since 1978 so they are not exactly fly by night.
US Food and Drug Administration (FDA) inspectors visit Biocon’s facilities. The only dings I found were for pre-approval of new facilities.
You may have been a little early for max peak. I have been taking Biocon sirolimus for some time but I am switching to Zydus when I run out of Biocon.
I will bite the bullet and take a test, that I have been procrastinating on, in the next week or two. I will be fasting except for my intake of grapefruit juice before and after 10 mg taking Biocon/Rapacan sirolimus tablets. I will try to get tested in 2 to 2.5 hrs after ingestion. Cannot promise the exact time because my local Lab Corp is sometimes a little slow seeing patients even if they have appointments. I will let you know the results.
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This is exactly my problem - I’ve gone in and waited for 2 hours sometimes, other times its 30 minutes… so for the sirolimus test it would be really hard to catch the peak level.
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I’ll keep the exact time from the time I take the tablets to the time they draw blood.
Are we still using a Life Extension phone in to secure a Sirolimus blood test from Lab Corp?
Very important point, especially when wanting to time a peak blood draw.
Life Extension / LabCorp worked for me as recently as a few days ago.
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I plan to post more extensively about my rapamycin journey (when I find some time, soon I hope), but just want to share that I now have the results of 2 sirolimus blood tests. After being on rapa for nearly 9 months I took a break when I realized it was slowing my healing from hernia surgery. After being off rapa for about 3 weeks, which I figured would put me in a major trough state, I did the blood draw for sirolimus in early August,2022. The result was <0.5 ng/ml, which I assume means no more than a trace.
I immediately went back on rapa and in fairly rapid increments upped the dose to 12 mg once per week. Seven months later I did the blood draw again and just got the results today. The result came with the word ALERT written in Red, and the result was 42.4 ng/ml, more than twice the upper end of the reference range. I took the 12 tablets immediately after eating an avocado, and immediately after ingesting the rapa I ate a large handful of peanuts swimming in olive oil. (Usually I just have rapa with a can of sardines in olive oil.) The blood was drawn 1 hour and 34 minutes after ingesting the rapa. Some quick google research seems to indicate that high blood levels of sirolimus are NOT a problem (and MB would likely say it’s a good thing, perhaps especially for an old geezer like me). Anyone see a problem with this high a result? Has anyone else received this high a result or close? If so, did it concern you and did you make any adjustments? As one of the ancient ones on this forum, I am resistant to lowering the dose but would appreciate the thoughts of others.I have not decided between carrying on with 12 mg/weekly or switching to 20 or 22 mg every 2 weeks to have a bigger peak - trough difference.
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Was the test done after 2 weeks break after the last dose and right before another dose? If so, your result shows that after 2 weeks without Rapa you almost don’t have any traces of it in your blood. I interpret it as good because the purpose of a break is to clear it out of your body.
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The range that you provided (between 3 and 20) is for transplant patients only. It shows the level of immunosuppression. If the trough is between 3 and 20, it’s considered enough to keep transplanted organ safe. It does not apply to those who take Rapa for longevity (nobody knows what trough has to be for longevity). For transplant patients, the trough is measured 24 hours (not 2 weeks!) after the last dose and right before the next dose.
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Why did you decide to switch to Zydus and have you seen any difference from the Biocon in terms of blood tests or any other metrics?
That is a very old post from my early days of experimenting with rapamycin
Over time many
have tried both and the results are similar. On a third-party lab test, they were essentially the same. I have been using Biocon for almost two years because it is significantly cheaper than Zypdus from my supplier. I am happy using Biocon.
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