AgingDoc and Kaeberlein Technical Discussion on Rapamycin

David Barzelai’s show notes for this podcast: https://www.barzilaiconsulting.com/rapamycin

More about the N of 1 high doses experiments with rapamycin: One User Trying Very High Doses of Rapamycin, and Negative Adverse Events / Results

other discussions:

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I found this interesting… David Barzelai’s estimate of how the mouse trial rapamycin dosing translates to humans (not just using simple allometric scaling) (from his podcast notes and twitter posts in the past): https://www.barzilaiconsulting.com/rapamycin

In 2000, I performed and posted a detailed back-of-the-envelope calculation of allometric conversions between mice and humans. Rather than focusing on strict mouse vs. human weight allometric conversion, I felt it may be more accurate to utilize serum concentration as the markers of comparison between rodents and humans. The objective of my calculation was to make a best estimate [read: “best guess”] for what dose for could hypothetically have some geroprotective therapeutic effect in humans.

My assumption for these purposes was that the ITP average serum level of rapamycin with daily dosing should ideally be the minimum peak levels arrived at by intermittent dosing of rapamycin in humans. A third assumtion is “high” dose in the mouse translates to 42 PPM sinc this was the highest dose seen in the rapamycin ITP study through the the centers of the Interventions Testing Program in genetically heterogeneous mice, at their highest average dose of 42PPM [As noted above, other work has increased lifespan up to a full 9x higher then that 42PPM highest ITP dose, with only slight decrease in lifespan that was nonsignificant in the females] to be a minimum level for human peak blood levels following PO sirolimus. The reader should note these calculations are based on hypotheses, and “best gueses,” no authority knows the true answer including whether rapamycin is efficacious as geroprotector in humans (I define “know” as justified to arrive at said conclusion).

Having made the arguments for high dose, it should be noted lower doses are better tolerated with a lower risk and side-effect profile, and suggestive work [using rapalog everolimus] by Joan Mannick suggests potential efficacy.

Rapamycin Dosing Calculation and Discussion - Human Dosing

This was posted on Twitter by https://twitter.com/agingdoc1 in an attempt to elevate the discussion around rapamycin (the post is found: 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:

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 u/PeterAttiaMD and as you can see Dr. Blagosklonny practices what he preaches in these videos showing 10 mg/week: Here

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) Publication URL Here

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 as reported Here

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 (Here) 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.

E.g., if someone takes 20 mg per week instead, sirolimus concentration >= the 10 mg dosing level for one full half-life (longer) as it gets eliminated, but OTOH at 7 days the Cmin trough would be higher too.

The frequency of 20 mg can be reduced or the risk of higher trough levels accepted.

Case report: N=1 of a ~120-130# patient definitely taking sirolimus 20 mg/wk, every week, with no problems & perfect biomarkers but less washout (e.g. less dose or frequency) has>risk, so YMMV.

The account was created in 2020 in part to increase geroscience awareness and elevate geroscience discussions.

( end quote from the threaded tweets)

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FWIW, I’ll add that Dr Rick Cohen said that taking rapa with a fatty meal would reduce the peak (slower absorption) while increasing the AUC (due to higher bioavailability). This is why he does not take rapa with fat.

As to whether the peak is more important than the AUC, I don’t know. But I now take rapa without fat or any food besides GFJ.

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