Bioavailability of rapamycin/sirolimus generics

Here is something from my RAPAMYCIN WISH LIST:
I wish someone would conduct (or fund) studies that would compare Rapamune with numerous brands of generic sirolimus on the following:

  1. Comparative rates of dissolution
  2. Comparative rates of absorption
  3. MOST important…compare intracellular levels of sirolimus at 1, 2, 3, and 4 hours following ingestion of an oral dose. This would tell us which generic brand or sirolimus is best transported across cellular membranes to the inside of cells…
  4. Or…is there a way to actually measure mTOR in cells and thus compare and measure levels of mTOR inhibition following a dose.

Just random thoughts, Ross

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The research on the nanocrystal technology that is used on the Pfizer rapamune formulation of rapamycin suggests a 27% improvement in bioavailability. Given this, it seems to be a nice bump, but not something that can’t be compensated for just by taking the generic rapamycin / sirolimus with a high fat meal.

Did you see the summary I posted here?

Yes but…how many of the generic brands of sirolimus are being produced using Elan’s or one of the other nano-technologies. And…if they are claiming enhanced bioavailability studies…I’d like to have access to the full text of the studies so I could examine them…

I’ve not been able to find any data on whether any of the generic brands use any of the nano-technologies, but given the extreme level of focus on cost for the generics I suspect none of them use anything like the proprietary nanocrystal / delayed release / increased bioavailability technologies that pharma companies are using in their long acting formulations.

These nanocrystal technologies are typically proprietary 3rd party technologies that are patented and expensive - which is ok in a drug still under patent and high priced, but probably its unable to recover the added cost of these tech, in off-patent drugs.

Thank you! I agree the cost of Pfizer isn’t worth the tremendous price difference unless you are one of the fortunate ones where money makes no difference.
Once again except for a few outliers like Rapamycin, real, life extension products will be unavailable to the poor. Even NMN (which in my opinion is problematic) costs me much more than Rapamycin from India.

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My book Rapamycin, mTOR, Autophagy & Treating mTOR Syndrome will be published on April 15th and available shortly thereafter. In my book I discuss alternative methods of inhibiting mTOR and activating autophagy…which I hope will be especially useful for people who cannot afford rapamycin. To order my book, go to: RAPAMYCIN mTOR AUTOPHAGY & Treating “mTOR Syndrome” - Life Extension

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Rapamycin, at $1/mg (or about $40 / month at 10mg/week) with the longest lifespan improvement of any compound tested in mammals - and as one of the cheapest, its without question the best bang for the buck that I think is available, or likely will be available, for the next decade…

I think this is the really under-appreciated factor that people don’t really recognize about rapamycin. its really, by far, the best game in town by a wide margin, in terms of healthy aging.


Ross - do you know of any way to test or measure or estimate of the amount of autophagy that is created via different mechanisms - e.g. rapamycin (at different doses), fasting for different periods, etc.?

Without this - its really hard to know how much autophagy we’re getting, how much to target, how much is optimal… its all so unknown right now… so much research still to be done.

“Monitoring and Measuring Autophagy”

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We are at the earliest stages of understanding a totally new area of science. Currently, I am not aware of any method that can quantitively measure mTOR inhibition or autophagy. There may be hundreds or thousands of mTOR receptors in individual cells. There is no way to measure how many mTOR sites are active, or how many are inhibited following a dose of rapamycin.

Measuring autophagy is also problematic. Autophagy is not one thing…it refers to numerous activities that target damaged cellular components and transport them to lysosomes for destruction and removal or reuse.

At this time, all we can do is track the amount of time an individual goes without ingesting nutrients, for example, a 16-hour fast vs a 24-hour fast. Longer periods of fasting will increase the relative inhibition of mTOR & activation of autophagy.

These are my thoughts…I’d be interested to hear what others have to say.

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Ross, I posted this on another thread;

Published in Personalized Medicine and Imaging| June 14 2017
“Noninvasive Measurement of mTORC1 Signaling with 89Zr-Transferrin”

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Hi Joseph,
Thanks for sharing this…it appears to be a very new technology. It is encouraging…but I don’t think it is any where near being able to be used by our “rapamycin community” to track our degree of mTOR inhibition. It will be some time before a test like this is something we can order on a lab test.

This is not new 2016

A person could do this type of testing the real issue is the cost, as this would NOT be an approved { medical billing] test. And these cost would be funded all “out of pocket”.

The testing used all off the shelf currently available components, the only issue is cost. The scan would cost around $3,000.00±

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In the cancer/Rapamycin/GFJ paper, they measured mTOR inhibition. Of course, this isn’t an off the shelf retail lab test.

Sirolimus Pharmacodynamics

mTOR phosphorylates p70S6 kinase (p70S6K) at threonine 389 which most closely correlates with activity in vivo(23). p70S6K phosphorylation at Thr389 was measured in peripheral blood lymphocytes (PBL) as a potential biomarker of rapamycin activity. Only subjects in the sirolimus alone study underwent determination of phosphorylated p70S6K. Blood for collection of PBL was drawn prior to sirolimus administration at baseline and analyzed again on week 1, day 2; week 1, day 4; week 2, day 1; and week 5, day 1. PBL were separated by Lymphoprep density centrifugation followed by isolation of CD3+ cells using Human T cell Enrichment kit (StemCell Technologies Inc., Cat # 14051A) The CD3+ cells were then treated with medium or PMA and Ionomycin for 1 hour. The cells were lysed and Western blots for phospho- and total p70S6K were performed. The results were analyzed using UN-SCAN-IT software and plotted using Sigmaplot. An indirect response model (24) with rebound effect (25) was used to describe our pharmacodynamic data and estimate the inhibitory effect of sirolimus. This model was built using NONMEM (version VII, level 1, ICON, Ellicott City, MD, USA) in conjunction with a gfortran compiler. First-order conditional estimation (FOCE) with interaction and Advan 8 were applied.

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