Yes, those are strange numbers given as harmful. Even taking the lowest, for a 70kg (roughly 150+lbs) person 0.5mg dose translates to roughly 35mg once a week. Well, in Mannick’s everolimus trial, they had an arm of 20mg a week, though it doesn’t seem like they bothered to adjust the dose for weight. And at that 20mg dose, they didn’t seem to have side effects significant enough to stop the intervention. It’s hard to be certain how exactly a 1mg dose of everolimus translates to an equivalent dose of sirolimus, but assuming, say, 1mg everolimus equals 0.75mg sirolimus you’d be looking at 15mg rapamycin once a week.
This is all complicated by dose scheduling daily vs weekly. Presumably you can’t just divide the weekly dose by seven to arrive at the daily dose and should instead use serum levels as a guide. Still, for example for the treatment of Pulmonary Lymphangioleiomyomatosis, you start off with a daily 2mg sirolimus. For transplant (kidney) patients there’s some weight adjustment, but the maintenance dose must be seen in the context of any other drugs taken concurrently, so that doesn’t tell us much in isolation.
Still, most people are using substantially lower doses of rapamycin for longevity purposes. If 20mg/1-week of everolimus or say, 15mg sirolimus is pretty safe, then odds are that 5-10mg a week is safe too. How long term hard to say, in animal models continuous lifelong dosage seems to still on average deliver health and/or lifespan benefits. If the same obtains for humans then in theory a 150lbs person could be on 6mg/1-week indefinitely. Transplant patients can be expected to be on a maintenance dose of rapa indefinitely.
So safety is an interesting metric to choose for rapa analogs, because as used for life extension, the current dosages commonly used seem safe enough. Do we need TOR101 to be “safer” than rapamycin when the latter is in the 5-10mg/1-week dose? How much safer do we need to be at that dose? Unless the idea is that the superior safety of TOR101 enables us to use higher doses which then translate into some tangible benefits compared to a lower dose of rapamycin and we’d love to go higher with rapamycin but sadly can’t because of safety.
Given the safety profile of rapamycin at the 5-10mg/1-week, you need to show me what those additional benefits of TOR101 are which are enabled by the higher dose. But I don’t see that specific issue explored in that presentation by Mannick.
It’s as if somebody observed that very high consumption of water can be dangerous, and therefore developed a liquid, WATER101 that you can consume without harm by the hundreds of gallons in a sitting. OK… but why would I want to, if consuming moderate amounts of water works fine for me? What benefits would I obtain if I were able to safely consume ten times more with WATER101?
That’s what needs to be shown. Right now, I don’t understand why I should be taking TOR101, instead of rapamycin in reasonable doses. But I might be missing something.
