Thread by @agingdoc1

Rapamycin dosing hypothesis:

This is just a hypothesis, needs testing: Severe mTORC2 inhibition is harmful (esp in males), but mild inhibition is ~neutral or possibly mildly beneficial in some settings (eg-cancer). This is a thread, keep clicking on msg to keep reading....

Advise 1st read in full includ. intro & discus. re: mTORC2 inhibition concerns (1) ncbi.nlm.nih.gov/pmc/articles/P… & (2) onlinelibrary.wiley.com/doi/full/10.11… (3) pubmed.ncbi.nlm.nih.gov/31577953/ (4) pubmed.ncbi.nlm.nih.gov/31373126/ (5) pubmed.ncbi.nlm.nih.gov/32720643/ (6) pubmed.ncbi.nlm.nih.gov/30794726/
@LammingLab & other great work

Problems w/ excess mTORC2 inhibition was mostly shown under:

1)Genetic⬇️eg, full/partial KO
2) Strong NON-rapamycin inhibition, eg RNA interference
3) non-WT or genetic eg murine models
4) HFD or kcal overfeeding
5) High rapa dosing➡️⬆️lipids,insulin,gluc, or other lab issues

There have also been other models raising potential conned a (eg, see onlinelibrary.wiley.com/doi/full/10.11… ) but most of these have been indirect or pathway based, w/o threshold for adversity & magnitude for rapa as Rx per se....(keep clicking until end for more)

While ⬆️ rapamycin doses in some cases⬆️survival even higher, despite worsening issues like glucose control (ncbi.nlm.nih.gov/pmc/articles/P…), others like I cited described poor outcomes, so potential concern remains. Also, people may be different- for better or worse, hence caution...

Some of these issues have been pioneered by @Blagosklonny such as here discussing in isolation some biomarkers may not be issues; broadly speaking as here ncbi.nlm.nih.gov/pmc/articles/P… or making a case for gluc. metabolism as a CR-like state of pseudodiabetes: ncbi.nlm.nih.gov/pmc/articles/P…

These arguments can be extended to lab setting vs life differences; Perhaps an OGTT anomaly is not an issue if the same patient at home has lower net-CHO /glycemic load mess and never actually gets those lab setting glucose spikes (provided good insulin, fasting glucose, HgBA1c).

Some of the studies I cited here including by @LammingLab *have* demonstrated at least some issues with glucose homeostasis besides OGTT under some rapamycin schedules in normal mice.ncbi.nlm.nih.gov/pmc/articles/P… -which also cited other pubs, though not all consistent nor w/big effects

Even if the pseudodiabetes argument is dismissed, that these labs may= poor surrogates for health,or that lab effects are modest & inconsistent as per the latest pub cited above data...& I add this data also hints HFD/overfeeding/obesity all greatly affect the lab results too....

As an MD my perspective on the labs generated in murine experiments is keenly focused on the implications *in practice*

Excess mTORC2 inhibition like other excesses (like even water!) can be harmful; we have seen that from models I described in the numbered list at the top...

...which leaves us with that latest pub I cited documenting glucose homeostasis w/ various rapamycin schedules. There, @LammingLab identified a dosing schedule whereby these effects were eliminated. In other work, he shows LE: pubmed.ncbi.nlm.nih.gov/27091134/
Which is great POC work...

This brings us back to the bedside, the clinical question, in humans. Current regimens (off-label, & let me hasten to add no proof of health lest of all LE in people at this point, through promising) emphasize complete rapamycin 1st space washout between doses....

This is to prevent feedback mTORC inhibition... and has also contributed to lower typical dosing indirectly for 2 reasons:
1) arbitrarily weekly dosing is easy to comply with hence sirolimus is only dosed so high so that the Cmin trough is below certain thresholds based on T(1/2)

2) more subtly, w/ rapamycin’s half life, concentration drops slowly, so higher dosing above a limit may as it washes out➡️mTORC2 inhibition no matter how infrequent the dosing (this may be mitigated a bit if as I hypothesize, that sirolimus levels are dropping⬇️this effect a bit

However (1) & above a certain level (2) both represent concerns re⬆️ dosing than the current standard (which was 5-6 mg pioneered by Dr Green & has been trending up, to 10 mg weekly by @Blagosklonny).

Of course as I suggest elsewhere, we could also, to a point, ⬆️dose by⬇️freq

But since this was already discussed in depth in my other long sirolimus thread (on dosing considerations), let’s examine the option of keeping dosing weekly but ⬆️dosing above 10 mg. Recall I discussed a case that tolerated 20 mg/wk healthy, great biomarkers...

Is this dose too high? Higher doses certainly come with ⬆️risk but life is a balance and the question is risk vs benefit. Increased inhibition of either or both complexes above levels makes sirolimus, an immunomodulator, more like an immunosuppressive. This is another focus...

Here, in this thread we are dealing narrowly with the starting hypothesis & its clinical implications if too (& how this ties to these dosing issues)...in the other thread it appeared 10-30+ mg sirolimus Cmax equivalents to the ITP gender/dosing study had the greatest murine LE

Note 10-30mg+ is just an ~ based on average weight, absorption, metabolism, etc. We are really discussing dosing to at least 23-80 ng/mL Cmax (ncbi.nlm.nih.gov/pmc/articles/P…), see my other thread which goes into the basis & conceptualizing dosing in mice more depth (I cite later)

Hence as I said before obtaining Cmin/Cmax is most helpful here... though recall these in some ways are truly minimal b/c those mice are doses DAILY, and though I’ve cited work showing intermittent dosing also➡️⬆️LE, it is not clear (1) vs. how much using same-study daily doses

& 2) remembering mice are different than persons not only broadly speaking for inference, but also translating mouse-time to human time: allometric approximations for time variables especially, & noting a day for a mouse being above a certain threshold of sirolimus as it washes

out is a lot longer in human terms and may govern a different effect ( it’s not just dose frequency that is allometric but how long “organism-time” above a threshold before it falls below it - ie, not a T(1/2) issue but the greater length of effective exposure per dose & AUC)

If this is not clear, before moving on, these are helpful following me:
1) ncbi.nlm.nih.gov/pmc/articles/P…
2) (ITP uses far better genetic cross-strain than C57BL/6J discussed): jax.org/news-and-insig…... note here, mouse-time varies by their age
3) ncbi.nlm.nih.gov/pmc/articles/P… >dosing alone!

So back to our discussion, these considerations suggest a multitude of reasons why 5 mg may underestimate effective dose, with al variables equal a minimum of 10-30+, maybe substantially higher doses (as suggested by some studies though not all realistic- eg, genetic models)...

Since the threshold for target Cmax is high & it is difficult to determine how high for optimal (including personalized risk/benefit), whether or not modest@mTORC2 inhibition is detrimental is pertinent to the weekly scheme (& even w/ less frequent scheme, if washout takes long)

A big difference between lab mice protocols & persons seen one at a time in the clinic is we can and should personalize & adjust to optimize *their* care. Recall from earlier, that the demonstrated harm seen outside of listed artificial settings was in the context of biomarkers

We also reviewed the constrains for current dosing perceiving complete washout as a need...& finally we discussed while there are many unknowns we are likely to be under dosing, perhaps profoundly so...so bringing this together, we consider may accepting a little mTOR inhibition

...provided there are adequate systems for biomarker monitoring (like lipids, insulin, HgBA1c, CBC, etc) and these values indicate that the slight inhibition is not operationalized in concerning ways for that patient. Recall our middle aged guy taking 20 mg/wk?...

Has wt ranged 115-130#, usually <125. And was absorbing the rapamycin with the Cmax/min to prove it (taking generic Rapamune=sirolimus); with no subjective or objective issues his response is clearly different than some others. He has also taken solitary doses up to 34 mg...

He may be an anomaly (OMAD, mild CR) though the literature has for single exposures seen dosing up to 120 mg sirolimus (one time) (though one case of 150 mg *may* have been a/w afib); a case w/ a beautiful curve of sirolimus 103 mg OD case 127.6 μg/L at 24 hr & minimal lab...

Anomalies as seen here ncbi.nlm.nih.gov/pmc/articles/P…. The point is not that this is safe - nor does this resolve the optimal frequency but it does underscore variability in tolerance....immunosuppressive effects are real risks and there is lots of literature but ambiguity given

much of this literature is in sick or transplant patients or N=1 which ( like my described case) are hard to make inferences ( except it is safe to say that in the case - with proven sirolimus concentrations described, the case breaks the rule and individuals are unique)....

So:

1) Rather than complete washout, we may be OK w/ sirolimus dosing at higher levels w/excellent biomarkers, signs/symptoms (exception: obviously a trough above certain immunosuppressive threshold pose too high risk in healthy persons even if these are great) to ⬆️Cmax....

So eg, 20 mg/wk or 30+ mg over long periods if the biomarkers (including some reasonable Cmin threshold) & all other data are excellent for at least some pts (the insert suggests limiting to 40 mg/day; dose-escalations have been tested at up to 15 mg/m2; 21 mg/m2 for boluses)....

...may be considered case-by-case depending on how that individual patients responds and all the other factors that go into personalized medicine (risks/benefits, risk tolerance and preference, comorbidity, etc)...

And on the research front 2) a concerted effort should be made to not only identify condition responses to dosing schedules but also risk metrics for both schedules (dose & frequency) & biomarkers including Cmin trough and others.

3) We need hard outcomes not only for safety, but just as vitally for efficacy. ***After all if it doesn’t help, why take on the risk*** Thus the under-dosing issues raised here are serious matters & perhaps the safest dose is one that at least approaches 10-30+ mg if possible.

The other lengthy thread re: rapamycin dosing I referred to above was:

https://twitter.com/agingdoc1/status/1310159741776203778

but b/c it is stacked this may be easier:
threadreaderapp.com/thread/1310159…

The thread you are currently reading is

https://twitter.com/agingdoc1/status/1310948171095433217

so presumably unrolled at threadreaderapp.com/thread/1310948…