ITP drugs dosing

Does anyone have a good sense of how to translate mouse dosing of agents from the ITP to humans?
I’d initially tried to convert to the mouse chow PPM to human equivalent by trying to figure out the mass of food that a human ate on a regular basis. Then in the methods section of the ITP paper on aspirin (Nordihydroguaiaretic acid and aspirin increase lifespan of genetically heterogeneous male mice - PMC) there’s a blurb:

Aspirin was obtained from a local supplier and used at a dose of 21 mg per kg of food. 4-OH-PBN was synthesized in the laboratory of Robert Floyd and used at a dose of 350 mg per kg of food. On the assumption that each mouse weighs 30 gm and consumes 5 gm food/day, the estimated daily doses of these agents would be NDGA 417; NFP 33; 4-OH-PBN 53, and aspirin 3.3 mg/kg body weight/day.

So: 21 ppm (1 million mg in a kg) works out to 3.3 mg/kg per day per their description, so you divide the ppm by roughly 6.4 to get the drug dose per kg. So, for a 70kg person, that would be roughly 231 mg of aspirin a day. Similarly, for the rapamycin stage 2 dose of 42 ppm (best efficacy), we are looking for a dose of 462 mg of rapamycin daily.

Even the 4.7 ppm dose would work out to something like 50 mg a day, which would be orders of magnitude more than what most people (6 mg once a week?) are doing.

Can anyone poke holes in my reasoning here? Is my math wrong? Does anyone have any insight into mouse metabolism or pharmacokinetics that would argue against translating the dosing in this way?

It should be emphasized that the common perception of scaling of dose based on the body weight (mg/kg) alone is not the right approach. This is primarily because the biochemical, functional systems in species vary which in turn alter pharmacokinetics. Therefore, extrapolation of dose from animals to humans needs consideration of body surface area, pharmacokinetics, and physiological time to increase clinical trial safety.

A simple practice guide for dose conversion between animals and human - PMC (nih.gov)

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Below is a summary table from EFSA (European Food Safety Authority), showing the basic convention they use to convert from PPM to mg/kg bodyweight in mice and rats depending on how long a drug is administered. After doing this calculation you would then apply allometric scaling using the table from post 2.

Researchers may apply more strain-specific calculations as well.

With regard to basic allometric scaling, it’s known to provide the best estimates for drugs that are primarily excreted through the kidneys.

Source PDF for EFSA information:

https://efsa.onlinelibrary.wiley.com/doi/pdf/10.2903/j.efsa.2012.2579

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Very helpful. Thanks for these posts!

It is nice that the 0.15 mg/kg EFSA conversion guidelines tracks closely with the aspirin manuscript.
To convert the aspirin dose for a 70 kg human, we are looking at 3.3 x 0.081 x 70kg = 18.7 mg.
This is a low dose in human terms, but could have a physiologic effect.

For rapamycin, then 42 ppm dose would convert to 37 mg daily. Still a very high dose in human terms.
The 4.7 ppm dose would covert to just about 4 mg daily. A more understandable human dose, but again much higher than most people are taking? Should people who are using rapamycin be dosing higher?

Just in case it’s relevant, the above discussion is theoretical from my end. I’m not recommending that anyone go ahead and take a lower or higher dose (or any dose at all).

There was one trial which looked at weekly dosing and still had a benefit for median and maximum lifespan.

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Can you provide a reference? Would love to dig into it.