Rapamycin dosing 10-30 mg discussion

This was posted on Twitter by @agingdoc1 in an attempt to elevate the discussion around rapamycin ( the thread is here:   ).  On Twitter, after reading each portion you keep clicking on the content to read the next part of the discussion (there is a word limit, so the post was broken up into a series of parts sequentially stacked).  Should this be useful it has been also compiled (with a few edits here and there) below into one post.  I hope you find it valuable:

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The following is for educational purposes only, and not medical advice.

@Blagosklonny is a pioneer in rapamycin research and was the first to propose it has the potential to extend life based on its mechanism of action; this prediction was subsequently confirmed in model organisms including but not limited to Saccharomyces (yeast), C elegans (nematode worms), Drosophila (fruit flies), and mice.

Rapamycin, also called sirolimus, has been used off-label (for non-FDA indications) for theorized healthspan and/or lifespan by such celebrities as @PeterAttiaMD and as you can see Dr. Blagosklonny practices what he preaches in these videos showing 10 mg/week: https://bit.ly/349jlpM .  

The discussion that follows puts this in some respects very modest dose in perspective and provides a framework for thinking about dosing (more or less – in the 10-30 mg rapamycin range).

Some background follows in this stacked thread:

In the ITP for 42 PPM, male mice sirolimus concentration=23 ng/mL (23% median LE, 8% max) & for females 80 ng/mL (26% median LE, 11% max) https://bit.ly/335VZBM

In one study (mostly males, mean 79.6 kg ~175#) subject Cmax ~23ng /mL with 10 mg of sirolimus (+/- ~7 ng/mL).  Cmax varies substantially by person & setting, so measuring and monitoring Cmax & Cmin is far more accurate https://bit.ly/3mW8uIk

So, 42 PPM in mice ~10-35 mg of rapamycin for the average 79.6 kg pt (0.125 mg/kg to 0.44 mg/kg). 

While the ITP mice mostly sustained the concentrations by daily dosing, in persons Cmax is achieved within 1-2 hrs & washed out to a trough corresponding to its half life (~65 hrs in this study; 55-85 in others).  So the AUC and sustained dose duration are substantially higher/longer in the mice though the implications of these differences and the validity of any extrapolations represent unknowns that are matters of both great speculation (https://bit.ly/2GgBt8x) and ongoing investigation.

Everything is a tradeoff – of knowns/unknowns, and risks/benefits.  For example, a higher dose would achieve a higher Cmax and also a higher AUC and a more sustained dose above a given concentration threshold.  Higher doses also have associated greater potential risks, side-effects, and imply less frequent dosing to allow sirolimus wash-outs to diminish potential side effects ( excess mTORC2 inhibition sequela, excess immunomodulation, etc.):

There is nothing magic about weekly dosing, it can be higher doses taken less frequently – but the implications of such tradeoffs are mostly black boxes.  In 2020, long-term transplant rejection prophylaxis therapeutic drug levels are 12-20 ng/mL and 5-15 ng/mL for lymphangioleiomyomatosis.  

@Agingdoc1 was created in 2020 in part to increase geroscience awareness and elevate geroscience discussions.