It’s all a crap shoot without the data. Just saying, if Matt K claims the bioavailability is low due to acidic pH in the stomach, then simply taking it after a meal might level the playing field (Rx tabs vs compounded caps). Yes, we need data for sure.
Getting ahold of the study MK mentioned showing 4-fold reduction in bioavailability of compounded rapa would be a good start, but I’ve never even seen an abstract for it.
And a high fat meal, increases by approx 30% apparently. If cost isn’t an issue, you can of course increase dose.
At this point I’d just like my 8 year old dog to be getting the most out of his compounded rapa Rx, but there’s just no way to know. I think it’s time to start importing the tablets for him myself
Here is an old (2004) and interesting study on dosing protocols on an angiogenic cancer mouse model.
Dosing of rapamycin is CRITICAL to achieve an optimal antiangiogenic effect against cancer
https://onlinelibrary.wiley.com/doi/epdf/10.1111/j.1432-2277.2004.00026.x
“Rapamycin has antiangiogenic activity against tumors. This has been discussed while addressing the problem of cancer in organ transplantation. Here we investigated effective dosing schedules against tumors and angiogenesis. Growth of established CT-26 colon adenocarcinoma tumors was measured in Balb/cmice treated with total equivalent rapamycin doses (1.5 mg/kg/day) given once a day, once every 3 days, or by continuous infusion. Tumors were MOST inhibited with continuous rapamycin infusion, and LESS BY BOLUS dosing. Interestingly, however, continuous dosing produced the lowest rapamycin blood levels(15 ng/ml). As rapamycin sensitive p70S6-kinase intracellular signaling is critical for angiogenesis, p70S6-kinase activation was measured in endothelialcells by Western blotting. Maximal p70S6-kinase inhibition occurred from1–5 ng/ml rapamycin. These same rapamycin concentrations optimally blocked vessel-sprouting from cultured aortic rings. Therefore, low-level rapamycin dosing most effectively controls tumors in mice. Importantly, antiangiogenic rapamycin levels are compatible with immunosuppressive doses, supporting its potential use in transplant patients with cancer”
Rapamycin treatment (ME: interesting, no dietary delivery) was initiated for the remainder of the experimental period under three different dosing schedules that delivered the same total amount of drug over the test period:
(i)1.5 mg/kg/day, intraperitoneally (i.p.)
(ii) 4.5 mg/kg once every 3 days i.p.,
(iii) 1.5 mg/kg/day by continuous infusion using an i.p. placed Alzet pump
Taken together, we suggest that the effectiveness of rapamycin as an anticancer agent falls into two primary dose ranges, where low ng/ml concentrations of drug produce a potent antiangiogenic or potential anti-proliferative effect, and higher doses which can serve to have a direct cytotoxic effect on tumor cells (Fig. 4). Importantly, with regard to the use of the drug in trans-plant patients, the antiangiogenic dosing profile of rapamycin appears most compatible with normal immunosuppressive therapy.
Finally, it is interesting to consider the observation that continuous delivery of rapamycin provided the most effective in vivo treatment regimen.
This finding is similar to what has been observed with other known antiangiogenic agents, where low-level continuous-delivery methods induce the greatest anti-tumor effect [17–19]. The advantage of this type of therapy is that side effects tend to be low, making it possible to use this approach over along period of time to maintain constant ‘pressure’ against tumor expansion. It is notable that as antiangio-genic effects are directed against normal vessel cells, and not cancer cells, drug resistance to this form of therapy is less likely.
However, an antiangiogenic approach to tumor therapy is not without pitfalls. In particular, if the antiangiogenic agent is not also cytotoxic at the concentrations used, nests of cancer cells not large enough to require angiogenesis will continue to exist"
Surprised at the significant effects of the dosing protocols. The high dose every 3 days produced the poorest result compared to constant LOWER dosing? Namely, higher peak and higher likely trough. No measurements of TOR1 or TOR2 blunting, would have been very beneficial.
Meaning for translation in humans? Take rapamycin smaller doses higher frequency for lower peaks/trough, vs higher doses spaced father apart but more side effects? How about taking Everolimus, with shorter half life, smaller doses more frequently? Perhaps more potency, less side effects? Or just maintain a MIN trough level, however the rapalog/modality, but without side effects? And which side effects acceptable? Minor and/or lipid/CBC dysregulation?
I wish we had a readily available assay for mTOR inhibition: “70S6-kinase:rapamycin inhibits this signaling pathway because mTOR, which is blocked by rapamycin, is an upstream regulator of p70S6-kinase. Phosphorylation at the Thr389 site correlates with p70S6-kinase activity”
These findings could be a metabolism translation issue…mice have super high metabolism (ie cancer proliferation), and clear rapamycin very quickly, so any “gap” in rapamycin gives cancer cells a chance to proliferate (1). But even transient treatment of mice with rapamycin mid life (albeit continuous), can increase lifespan 60% (MK, 2016)
(1) Blood levels of rapamycin in IP injected mice goes from 1800 ng/L to 45 ng/L in 24 hrs.
An MK paper (2016)…6 YEARS AGO, he postulates about rapamycin regimen, dose, formulation
Rapamycin in aging and disease: maximizing efficacy while minimizing side effects
“Moving forward, we believe an emphasis should be placed on understanding how to achieve maximal efficacy from rapamycin treatment while minimizing side effects. While eRAPA and injected rapamycin are not directly comparable, as the delivery methods will have different pharmacokinetic parameters and may result in dramatically different tissue distributions, these results provide an initial foray into examination of dosing and delivery of rapamycin in a preclinical model of a medically relevant class of disease”
Yet what has changed, what have we learned in human translation since then? Pretty much nada…simple oral dosing to “max tolerable side effects”, and we don’t even know which side effects are acceptable long term?
“dramatically different tissue distributions”…indeed, but as yet unexplored.
We have no readily available tissue or blood or other assays for TOR or p70S6-kinase, or fully validated/translatable epigenetic aging, one of Peter Attia’s rapamycin concerns…“we have no good clinical biomarker”
Although they did measure an mTOR signal in the seminal cancer/rapamycin/GFJ study: “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”
Good stuff MAC. Thanks.
I like the low dose prevent angiogenesis and reduce cell proliferation approach. Granted, it may not have the cytotoxicity, but no metastasis without angiogenesis.
I sort of like the everolimus short half life twice a week regimen. I’m still not clear on its affect on TOR 2.
Both of these rapalogs will definitively will trigger TOR2 disruption with sufficient high dose and chronic dosing, well documented. But Everolimus, mechanistically, does have a higher affinity for TOR2.
Everolimus “might” offer a superior different dose/AUC/side effect tradeoff. The Mannick study of Everolimus (2014), showed that 0.5mg/day was well tolerated.
From a “brief” scan, it appears everolimus might confer fewer side effects (CBC, lipids), but would have to be careful to compare equal AUC/potency. Everolimus requires approx 2X the dose of sirolimus to achieve similar trough.
I am taking a deeper comparison, will post something on the Everolimus vs Sirolimus topic thread.
Certainly coming off patent and being very low cost compared to Rapamycin makes a close look worthwhile.
Do I have this right?
Everolimus
Pros: short half life
may be able to dose it higher and even twice a week
fewer side effects ( lipids,glucose)
Cons: need a higher dose than rapa
hits TOR 2 even harder
a little more expensive
the longevity effects haven’t been studied as much as rapa
Would agree with what you’ve briefly summarized. Also some indication Everolimus better at crossing BBB. Is perhaps taking more frequently a con? The harder TOR2 perhaps at very high doses…cancer/transplant, not at lower doses? Dysregulating TOR2 would more amplify side effects, including TOR2 specific insulin signalling/hyperglycemia. Of the comparative studies, not many report higher hyperglycemia with Everolimus…but similar range of side effects as rapamycin.
Re cost, I was quoted by an Indian supplier $0.7/mg for Rapamycin ($7 for 10 x 1mg/tabs), and Everolimus $.95/mg ($95 for 10 x 10mg tabs). If you’ve got to take 2X the Everolimus dose for same potency, then effectively $1.80/mg vs $0.70/mg, 250% more. On a total cost basis over a year if it really increased lifespan…meaningless.
It’s slightly better side effects profile, that could be the lure/incentive.
I’ve only found a few longevity studies on Everolimus. One showed an increased lifespan of 85% (1). Everolimus works so VERY similarly mechanistically to rapamycin, and according to Dr B, would deliver “equal lifespan enhancements” to Rapamycin, potency equivalent. More clinical trials seem to be using Everolimus and Tacromilus recently over rapamycin…better side effect profile as a chemo/immuno adjuvant. And in reality, rapamcyin has a poor record in existing cancer trials in terms of cancer mitigation or transplant rejection.
https://sci-hub.se/https://doi.org/10.1016/j.yexcr.2014.04.012
The article also says that c/w rapamycin, everolimus stimulates mitochondrial oxidation. What am I missing here? Do they mean increased mitochondrial stress from reactive oxygen species?
The increase in propensity for TOR 2 inhibition is also concerning.
Perhaps they mean that everolimus increases mitochondrial oxidative capacity. That would be a positive.
The reference:
“Shows that everolimus alone has the potential to stimulate mitochondrial energy metabolism, while sirolimus has negative effects”
That’s a lean for everolimus but still the majority of longevity studies are with rapamycin. Are we sure that everolimus would do the same?
I’ve seen quotes for Everolimus from $60 for 10 x 10mg tablets ($0.60/1mg), to $107 for 10 X 10mg ($1.07/mg). As noted, dosing mg/day needs to be increased by 50% to 100% over rapamycin doses for similar efficacy (see this information from Lloyd Klickstein interview)
Find the note the above post by @MAC regarding the “Highlights” interesting, where 4. Everolimus distriubutes differently into tissues and sub-cellular components.
I think an argument can be made for alternating everolimus and rapamycin to get maximum tissue coverage (in terms of mTOR inhibition).
More info on Everolimus in this thread: Everolimus instead of Sirolimus / Rapamycin? Anyone else trying?
Pricing Quotes for Everolimus here: New Price Quotes for Rapamycin and Everolimus
I’d never given the above review paper a good read. There are some very interesting findings/comments. If you go through it carefully, the author gives Everolimus the edge, especially clinical trials. It has superior efficacy in various important pathways, and fewer side ADE (Adverse Events) (eg. rejection, lipids).
Although there may not be many everolimus/mouse models and longevity, there are tons of clinical trials in humans (thousands++ patients), just like rapamycin. You’d think we’d know if any negative signalling by now?
Everolimus and Sirolimus in Transplantation-Related but Different
A couple of interesting findings:
From this study, they conclude:
https://www.jstage.jst.go.jp/article/dmpk/24/2/24_2_175/_pdf/-char/en
“Taking these findings into consideration, cyclosporine has a more profound effect
on everolimus than sirolimus pharmacokinetics and our patients may need a considerably larger dosage of everolimus due to the lack of pharmacokinetic interaction with tacrolimus.”
So this is in the context of COMBINED Cyclosporine/Rapalog, NOT rapalog only. There is HUGE drug-drug interaction at play. What about head to head, no other immunosuppressants??
In this study:
Everolimus Inhibits Anti-HLA I Antibody-Mediated Endothelial Cell Signaling, Migration and Proliferation More Potently than Sirolimus
“Notably, the recommended levels of everolimus are lower than for sirolimus, consistent with
our findings that everolimus more potently inhibits mTOR and related signaling”
So it seems lower trough levels for Everolimus than Rapamycin, which may or may not require a different dosing for same trough. But not a clinical translation impediment in any way.
“Nevertheless, at the clinically relevant concentrations tested, everolimus was much more effective in inhibiting class-I-stimulated mTORC2 activation by dissociating Rictor and Sin1 from mTOR. This included more effective inhibition of class-I-stimulated AKT phosphorylation and inhibition of ERK phosphorylation, an ability that, remarkably, sirolimus lacked”
Animation above shows Everolimus more effectively blocking mTOR2, and ONLY Everolimus blocks AKT/ERK?!
But what is AKT/ERK?
"The AKT and ERK signaling are both aberrantly activated in a wide range of human cancers and have long been targeted for cancer therapy. During the process of tumorigenesis, a cell escapes from normal control of growth and acquires capability of invasion. Aberrant activation of the PI3K/AKT and/or MAPK/ERK pathways promotes cell survival and unlimited growth and proliferation, driving carcinogenesis. Only two PI3K inhibitors (idelalisib and copanlisib) and two mTOR inhibitors (temsirolimus and everolimus) have been approved by FDA for clinical treatment of cancers "
So is this unique interaction of Everolimus vs Sirolimus clinically relevant for longevity via cancer suppression??
mTORC1 and mTORC2 in cancer and the tumor microenvironment
“Although mTORC1 signaling has been extensively studied in cancer, recent discoveries indicate a subset of human cancers harboring amplifications in mTORC2-specific genes as the only actionable genomic alterations, suggesting a distinct role for mTORC2 in cancer as well. While mTORC1 is extensively studied in cancer, recent reports also demonstrate a distinct role for mTORC2 in prostate, breast, and lung cancer, glioblastoma, and T-cell acute lymphoblastic leukemia…reinforcing the importance of mTORC2 signaling in cancer and as a potential target for inhibition”
This sounds like a meaningful signal to inhibit at some level…mice only die of cancer, so isn’t that the implicit translation to humans we are all hoping for??
Is it possible, that the long lived mice on rapamycin are really achieving this lifespan attainment by additional to TOR1…inhibition of mTOR2? Consider they are on chronic administration, so certainly plausible? And it’s only because researchers DO NOT UNDERSTAND what TOR2 really does or READILY MEASURE, that this pathway is really underpinning some of the lifespan extension? It has been theorized by many of the leading researchers (MK/LAMMING), but dismissed as taboo due to enhanced side effects associated with interaction with TOR2. But what about harnessing some of this for human translation?
Here is a dose escalation study of Everolimus (still want to compare to a similar head to head Sirolumus)
Tolerability and steady-state pharmacokinetics of everolimus in maintenance renal transplant patients
https://sci-hub.se/10.1093/ndt/gfh322
" The primary objective of this multicentre, randomized, double-blind, placebo-controlled, dose escalating phase 1 study was to evaluate the safety and tolerability of everolimus at four dose levels (0.75, 2.5, 5 and 10 mg/day) in maintenance renal transplant patients receiving cyclosporin and steroids. The secondary objective was to assess the pharmacokinetic profile of two different formulations (capsule and tablet) of everolimus."
As you can see, after an initial drop in platelets and WBC, at 42 days out, 0.75mg/day or 2.5 mg/day do NOT result in significant changes (modest?) in these parameters, as well as cholesterol and TG.
A 0.5 mmol/L rise in cholesterol is about 20 mg/dL. A 0.5 mmol/L rise in TG is approx 45 mg/dL.
What about AUC, and comparisons to Sirolimus?
At 0.75mg/day Everolimus (5.25mg/week), this is dose equivalent to about 5mg/WEEK of Sirolimus. 5mg/week of Sirolimus (no GFJ) has an AUC-infinity of about 676 ng-hr/mL. There is not AUCinfinity reported to Everolimus at 0.75mg/day, only AUC24 of 228. Extrapolating to infinity, it would be higher. Certainly at 2.5 mg/day, AUC24 of Everolimus is already at 570 ng-hr/mL.
From what I know so far, I would have no qualms switching from Rapamycin to Everolimus. Potentially offers a better cancer suppression efficacy? Possibly lower dose/side effects? The clinical trials give it an edge over Sirolimus. Possibly higher LONGEVITY?!
Part of my rationale is a long term view…if I’m going to take this drug for potentially decades, side effects is a very big deal in terms or risking some other deleterious pathway. But I want my cake and eat it too…maximal impact on growth/cancer suppression, yet few side effects. CVD, immuno, infections, which plague high dose rapamycin, and potentially critically limit maximal human longevity translation?!
The Mannick 2014 study using Everolimus at 0.5mg/day or 5mg/week was well tolerated. You’d think if the researchers had ANY concerns about Everolimus safety, they certainly wouldn’t have chosen it for an eldery (n=1218, > 65 yo) population!
https://sci-hub.se/10.1126/scitranslmed.3009892
At time of writing, I am still working through my exploration with Rapamycin, but always on the hunt for something better. Everolimus might be a better train to hop on.
Everolimus is better than rapamycin in attenuating neuroinflammation in kainic acid-induced seizures
Conclusions
“Rapamycin and everolimus can block the activation of inflammation-related molecules and attenuated the microglial activation. Everolimus had better efficacy than rapamycin, possibly mediated by the inhibition of ERK phosphorylation. Taken together, mTOR inhibitor can be a potential pharmacological target of anti-inflammation and seizure treatment.”
There’s that ERK thing again!
Sirolimus and everolimus in kidney transplantation (2015)
https://sci-hub.se/https://doi.org/10.1016/j.drudis.2015.05.006
“Everolimus is more widely used than is sirolimus, and is now extensively used in combination regimens with tacrolimus.”
Very comprehensive. The graphs are very noisy but I think I get the message.
In the Mannick study, I believe that the 5 mg per week was as effective as the 20 mg. Since one reason to switch to everolimus would be to up the dose, I’m not sure that it’s necessary, at least as far as immune response is concerned.
At 5 mg only about 4% incidence of increased cholesterol. Maybe same for triglycerides? What about glucose?
With a half life close to 24 hrs, you could hit it again at 4 days I guess.
I really like zero neutropenia or thrombocytopenia with the 5 mg weekly dose, the other side effects are no big deal.
I like the cancer inhibition for prostate, lung, brain and ALL. Of course, if you eliminate All cancers it only translates to an extra 3 years longevity, but still.
Are we now thinking that we actually want some TOR 2 inhibition?
Why hasn’t Blagosklonny or Matt switched over?
That’s a pretty big deal actually.
It’s getting tempting. So a real life example:
Day one 5 mg everolimus. It’s practically gone by day 3-4. So do we dose it again?
Day 7 rapamycin
Day 14 everolimus again
Is that how you see it?
What, all this work for 3 years…you referencing all cause mortality stats? You dismiss some of these pathways and mTOR inhibition dosen’t impact CVD or neurodegeneration?
Yes, shake things up!
What do they know…they’re in the same dart club as us. Dr B is captain mTOR, don’t think he’s got Everolimus qualms. Might just be access/cost?
