9 replies to this topic

[smithx]

Everolimus is now available, and I'm wondering whether it's better to take than sirolimus for life extension.

 

Some reasons it could be better:

 

• Because it has a shorter half life, it could be less likely to cause MTORC2 inhibition, which is what you want to avoid.
• Because of the shorter half life, a higher dosage (and more MTORC1 inhibition) could be possible, while still allowing a cycle time that avoids MTORC2 inhibition

On the other hand, I haven't found, in a bit of searching, definitive information as to:

• What is the relative amount of MTORC1 and 2 inhibition of the two compounds?
• What would be a reasonable dose? In rats, everolimus had 16% oral availability vs 10% for sirolimus (http://theoncologist...15/12/1262.full)
• What would be a reasonable dosage frequency (compared to sirolimus weekly or every 10 days)?

Does anyone have some good references or evidence that either is superior for lifespan / healthspan extension purposes?

 

 

 

[Andey]

Interesting topic

from https://www.ncbi.nlm...3932/#NOV152C67

Although relatively minor, the differences at C40 have important clinical implications. First, bioavailability and half-life are significantly different among the compounds (Table (Table1).1). Sirolimus and everolimus are taken orally each day. Comparative pharmacokinetics suggest that everolimus is more readily absorbed and exhibits greater oral bioavailability compared with sirolimus due to selective intestinal cell efflux for which sirolimus alone is a substrate.6,67,68 The relative hydrophobicity of sirolimus does have its own benefits because it is readily absorbed through the skin69 and is used in custom topical preparations to treat TSC-related facial angiofibromas.11 The various rapamycin analogs differ in hepatic metabolism, in which everolimus is 2.7-fold lower than sirolimus.70 Nonetheless, sirolimus systemic clearance is half that of everolimus,67,71 giving everolimus faster steady state levels after initiation and faster elimination after discontinuation. On a pharmacodynamic level, mTORC1 inhibition appears comparable at physiologic dosing ranges, but tissue- and organelle-specific differences have been observed. For example, there is evidence that everolimus, but not sirolimus, distributes to brain mitochondria and stimulates mitochondrial oxidation in the brain.72

 

Looks like everolimus could penetrate better into a brain due to less protein binding 75% vs 92% for rapamycin. Don't sure if it's that beneficial though, one could make an argument to take something to increase BDNF while taking mTor inhibitor for a brain. 

[QuestforLife]

The half life difference is by far the most important factor. With 30hours vs 60 hours (everolimus vs sirolimus, approx), you can double the dose and not suffer any worse side effects all other things being equal. You might want to be slightly cautious with this if absorption is greater with everolimus.

I'm almost 40 and to be honest 2mg a week is right on the limit of what I feel is beneficial for sirolimus. As you get older the ability of rapamycin to shrink cells and increase functionality is more valuable vs the blocking of cell proliferation. But for me I'd probably take 2-3mg of everolimus a week and be confident it would far more good than harm.

I thought everolimus had 4 or so years left on the patent, where can it be bought from now reliably?

[Andey]

The half life difference is by far the most important factor. With 30hours vs 60 hours (everolimus vs sirolimus, approx), you can double the dose and not suffer any worse side effects all other things being equal. You might want to be slightly cautious with this if absorption is greater with everolimus.

I'm almost 40 and to be honest 2mg a week is right on the limit of what I feel is beneficial for sirolimus. As you get older the ability of rapamycin to shrink cells and increase functionality is more valuable vs the blocking of cell proliferation. But for me I'd probably take 2-3mg of everolimus a week and be confident it would far more good than harm.

I thought everolimus had 4 or so years left on the patent, where can it be bought from now reliably?

  Its already manufactured in India. 

https://www.medplusm...mus-10-MG/25954

 

  Don't sure where to by it online though.

Edited by Andey, 30 June 2018 - 11:09 AM.

[QuestforLife]

I've made at enquiry at dropshipmd (where I bought a large quantity of rapamycin from).

[smithx]

I've made at enquiry at dropshipmd (where I bought a large quantity of rapamycin from).

 

They quoted me $15-$25 per 10mg pill, depending on quantity.

[VP.]

They quoted me $15-$25 per 10mg pill, depending on quantity.

That's pretty useless. It's dosed for transplants. 

[Andey]

It's not a coated tablet and could be divided to whatever amount needed(at least I do so). BTW its also manufactured in 5mg tablets too but I suspect price difference would be not 2 times less and well worth the effort of biting half a pill off. No need to be precise here as our messy biology would make bioavailability different even for ideally equal tablets.

 

Back to the thread topic:

I found another interesting study

Sirolimus and everolimus in kidney transplantation.

http://sci-hub.tw/10...dis.2015.05.006

1. Looks like bioavailability is similar 

Sirolimus  Cmax (SD) of 40.5  +-22.2 mg/L

Everolimus Cmax (SD) of 45 +-21 mg/L (both for 2.5mg oral dose)

Sirolimus is more bioavailable with food

https://www.ncbi.nlm...pubmed/10579146

while Everolimus is less

https://www.ncbi.nlm...pubmed/11837553

It would be interesting to know whether Everolimus increase its bioavailability when taken sublingually. Its one of the suggested routes of administration for Tacrolimus and it's recommended to cut the dose in half for it, meaning its 2x more bioavailable. 

One probable advantage is that sublingual route could mean its more available to the brain.

2. The study notes that there is no method of measuring mTOR inhibition quantitatively to compare two drugs, having that this is a pretty recent(2015) study means that we would not have this information for some time.

3. Due to different pharmacokinetics, two drugs accumulate differently. 

    Sirolimus: In studies in rats, considerable accumulation of sirolimus in

the heart, kidney, intestine, and testes was found, although
whether this is the same in humans is not known

    Everolimus: Animal experiments showed a high affinity of everolimus for thymus,

lungs, gallbladder, cerebellum, kidneys, and spleen. Data in
humans are not available.

 

Everolimus tissye affinity looks more favorable to me, but as I take it myself I definitely feel some urge to feed my confirmation bias) 

 

[smithx]

Thanks this is interesting:

 

Due to different pharmacokinetics, two drugs accumulate differently. 

    Sirolimus: In studies in rats, considerable accumulation of sirolimus in

the heart, kidney, intestine, and testes was found, although
whether this is the same in humans is not known

    Everolimus: Animal experiments showed a high affinity of everolimus for thymus,

lungs, gallbladder, cerebellum, kidneys, and spleen. Data in
humans are not available

 

 

 

Sounds like it could be good to alternate the two, to get better coverage.

 

 

[QuestforLife]

They quoted me $15-$25 per 10mg pill, depending on quantity.

They quoted me $500 for 30 x 10mg pills.

I'd say on balance it's still too expensive to be worth changing over from rapamycin.