I was wondering whether anyone here had any thoughts or insight into the possibility of taking very low doses of rapamycin on a daily/every few days basis?
I recently saw a slide from the RapaCat (Trivium’s feline HCM formulation) study, where they noted a reduction in myocardial thickness for the low dose group during the first 60 days of the trial before plateauing/slightly increasing. The rodent studies I’ve seen all seemed to involve ultra-low doses of rapamycin mixed into the daily feed, and positive outcomes were noted regarding lessening of myocardial stiffness, diastolic function, etc.
The study I’ve specifically looked at used 42 ppm over the course of eight weeks, so for a 30 gram mouse averaging an intake of about 5 grams of food daily this would mean a daily dose of 0.000205mg. I know the half-life in mice is significantly less than in humans, which I realise would affect the concentrations of rapamycin in the bloodstream. (My interest is for my cat, who currently is on 0.75mg or 0.15mg/kg once per week. Much like the high-dose group in Trivium studies, there has been no increase in myocardial thickening but no anti-cardiac remodelling either. Following this protocol, he’d be on 0.034mg/day or 0.24mg/week, significantly less than his current dose.)
Apologies for any maths mistakes or misunderstandings of the data, or if this has already been debated and ruled out. The rodent study lasted eight weeks, which tracks with Trivium’s findings at 60 days. But the mice were then taken off rapamycin and followed for a further eight weeks, noting that heart function remained stable, whereas no further improvements were noted in the HCM cats from that point on. So I wonder if there’s something to be said about lower levels of mTOR suppression or even a on/off cycling of use.
All the NIA ITP studies on rapamycin for longevity were dosed daily. In fact virtually all but a few of he mouse studies have been daily dosing. And results have been good. But of course, these mice live in Labs that are pathogen-free environments (so mTORC2 inhibition and immune supression are much less of an issue for the mice compared to humans and pets that live in the real world).
And in organ transplant patients (of which we have a number here on the forums) some of them take 1mg of rapamycin per day for a number of the days of the week, and that seems to have been working well for them (of course, they do it for immune system supression, which probably is not your goal). They take reasonable precautions to avoid crowds, etc. given their status, but it does “work” for them.
So yes - it is possible to do this type of dosing regimen. But I don’t think there are any doctors or vets that would likely recommend this for people or pets. Its the regular, chronic daily dosing of rapamycin that is generally believed to cause the mTORC2 inhibition and immune supression - and thats a risk that most people want to avoid. If you’re looking for some specific benefits for your cat in this type of dosing… it might be reasonable to try, but precautions would need to be taken (if its mainly a house cat, and doesn’t go out and cavort with the local neighborhood cats each night perhaps its lower risk).
There are many possible dosing regiments… once a day, once every two days, once every three days… but almost all the study data is only on daily dosing or weekly dosing.
From a practical standpoint - for people, most of the tablet availability is in the 1mg dosing. Everolimus is available in .5mg I think in some areas. And even with Everolimus at 1mg its equivalent to something like 50% to 80% the dosing of rapamycin - so you get some fractional dosing equivalents with Everolimus, but generally its harder to implement vs. just using discrete 1mg tablet increments.
For pet cats it gets even harder from a practical standpoint. Most rapamycin tablets can’t be divided or you lose the bioavailability of the drug (broken tablets will likely get destroyed in the stomach and won’t reach the small intestine to get absorbed). It sounds like TriumVet is the only group that may be offering small dose, encapsulated rapamycin for pet use.
Anyway - these are my thoughts. I’ve not studied the TriumVet information at all.
Thank you so much for your detailed and thoughtful input!
Before beginning, I had messaged Dr. Kaeberlein for advice on dosing and was told to remain under 0.3mg/kg per week – I suppose my line of thinking was, remaining under this threshold would it be safe to dose daily rather than all at once? My cat is on 0.75mg once per week currently, or 0.15mg/kg. This new dosing would be something like 0.05mg/kg, which I believe even with the half-life elimination time should be safe with a buffer day worked in. (We initially began with 0.1mg/kg and increased the dosage after not having noted side effects or anti-cardiac remodelling three months in, but I think the fact that there was no increase in thickness would indicate that this dosage had been effective, in light of the Trivium findings.)
I have good relationships with several veterinary compounding pharmacies, I believe I could work with one to get doses of 0.03mg by combining Rapamune with a filler. Given the results I’m seeking and the negative effects I’ve noticed with these higher doses, particularly an increase in hepatic enzymes and now liver inflammation via ultrasound, I’m willing to give this protocol a try.
One last question: I’ve read about so-called ‘rapamycin vacations’ and was thinking I’d give my cat at least a week off, to help reset his body. Is there any merit to this? I’m hesitant to leave it and have his HCM progress.
Thanks again for the help! As I’ve been using it only for my cat, I wasn’t sure whether anyone would be interested in our experience with rapamycin. One bit of data I can share is with regards to his ALT levels, which increased in direct correlation to his rapamycin dosages. I had switched him to Life Extension’s Bio-Quercitin last month, having previously used a custom compounded blend at 50mg daily, and his ALT dropped from 400 to 100 within three weeks.
Is this true? Before seeing the Trivium presentation, I assumed a lack of anti-cardiac remodelling meant that the enteric coating on the compounded capsules had failed. But having now seen that their ‘positive findings’ were primarily a stabilising of myocardial thickening as compared to the placebo group, which aligned with our results, I now believe it to be working effectively.
I wouldn’t be surprised if the enteric protection was less than the pharmaceutical coating. I had/have thought of taking the compounded capsules and Rapamune myself and having my serum levels measured, at least to have some means of comparing absorption rates.
Yes - we’ve heard a lot of reports from people that the rapamycin from compounding pharmacies is not getting through the stomach acids and becoming bioavailable in the bloodstream. See these two references: Bioavailability of Rapamycin From Compounding Pharmacy