One Week Rapamycin High Dose Test for My Dog; Schedule and Results

I did a higher dose rapamycin test with my dog just to see how she would respond. There were no significant issues, just soft/runny stools, and perhaps less energy (kept her in home mostly to reduce risk of exposure to any infections, etc. and she mostly just slept/lay down, not much different than normal).

My goal was just to test for tolerance and side effects as I ramped her up on higher doses, using 1mg rapamycin tablets (placed inside small cubes of cheese). It all seemed to go fine, as an initial short term tolerance test. No blood tests were done in this initial test, perhaps in future ones.

My goal was to get up to 1.6 mg/kg, but I only made it up to 1.4 mg/kg (just due to my own schedule and activities). But, as expected, no issues. My dog is 5 years old, 27lbs or so (about 12 kg).
The target dosing of 1.6 mg/kg is about 10X what is being done in the Dog Aging Project TRIAD program (.15mg/kg) - as described here: Rapamycin for Dogs

Here was my specific dosing schedule:

Dog Dosing Test #1 Mgs Dose mg/kg Date/Time Dosing Dinner
Day 1 4 0.3 Feb 18, 6:15pm, Sardines in oil, cheese, and kibble
Day 2 8 0.6 Feb 19, 2pm - 4mg, 7pm 4mg Cheese for 2pm dose, A friend fed her a bit on the walk, then I fed her the Rapa dose around 7pm with cheese, then some more dinner.
Day 3 12 1.0 Feb 20, 11:30am - 6 mg, 7pm - 6mg 11:30am - Mixed 6 Rapa tablets with Sardines (crushed in bowl). 7pm - gave Dog 6mg of Rap in cheese pieces.
Day 4 14 1.1 Feb 21, Runny stool in morning walk - so No dosing today, I was concerned Dog might have diarrhea in the house, and I was out all day. Dog not very hungry.
Day 5 16 1.3 Wed, Feb 22. 7mg at 9am, 8mg at 7pm Gave cheese with doses. Regular kibble for late dinner after 7:30pm.
Day 6 18 1.4 Thurs, Feb 23., 9mg at 10:30am. 9mg at 7pm. Cheese dosed with rapamycin 9mg in morning, 9mg at 7pm prior to dinner. Then regular kibble dinner.
Day 7 20 1.6 Friday. No dosing - dog with friend.

Here are my observations during the week, on a daily basis:

Dog Dosing Test #1 Mgs Dose mg/kg Date/Time Dosing Observations
Day 1 4 0.3 Feb 18, 6:15pm, Nothing abnormal. Sleep during night normal, Stool in morning normal, urination normal.
Day 2 8 0.6 Feb 19, 2pm - 4mg, 7pm 4mg Nothing abnormal. Sleep during night normal, Stool in morning normal, urination normal.
Day 3 12 1.0 Feb 20, 11:30am - 6 mg, 7pm - 6mg Trying to shift consumption of rapamycin to morning so less risk of sleep disruption. Also trying to dose with ā€œhigh fat mealā€ every time also (Sardines in Oil) instead of just cheese. 7pm - Rapa/Cheese pieces, and kibble for dinner.
Day 4 14 1.1 Feb 21, 8:30am - Took Dog for morning walk. Stool in morning normal, urination normal. 1pm walk - stool ok, but then turning runny and liquid at end. Not hungry for sardines at 1pm (tried to feed her). 7pm - runny stools. Dog ate very little, and little apparent hunger.
Day 5 16 1.3 Wed, Feb 22. 7mg at 9am, 8mg at 7pm Normal stool in morning so gave Dog an additional 7mg. Normal stool again in evening when I got home, so I gave her another dose - this time with 8mg.
Day 6 18 1.4 Thurs, Feb 23., 9mg at 10:30am. 9mg at 7pm. 9:30am - stool solid. Normal urination. 9mg rapamycin at 7:30pm.
Day 7 20 1.6 Friday. Friend said - dog had soft stools in morning. Low energy in evening. Little Hunger, or interest in food at dinner time.
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Isnā€™t the latest dog aging project a once a week dose similar to what many of us humans do? Were you dosing daily here? Why 1.6 mg/kg?

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Yes - and Yes, I was dosing daily. My target was to duplicate the higher dosing levels of the ITP study in mice; 42ppm (or about 1.6mg/kg by my calculations, in human terms and perhaps in dog terms, but Iā€™m not sure of the half-life of rapamycin in dogs.

I was surprised to learn on Thursday from Adam Salmon (the monkey/rapamycin trial researcher) that marmoset half-lifes for rapamycin are about 24 hours or so - so about half (or less) of what humans typically experience.

That dose is still far, far lower than the 378 ppm that theyā€™ve done in mice at their highest point for 3 months. So, for a week-long experiment it seemed to me to be quite safe and I was primarily interested in seeing what side effects would come up.

Here are the dose translations from the other rapamycin studies:

Sirolimus
Dose
Mouse
mg/kg/day
Dose
Mouse:
Blood/Sirolimus
Level
Human
mg/kg/day
Dose
Dose for 60kg Human Daily Dose adjusted for longer half-life (/4)
4.7ppm āˆ¼2.24 3 to 4 ng/mL 0.182 mg/kg 10.92 mg 2.73 mg
14ppm ~6.67 9-16 ng/mL 0.542 mg/kg 32.54 mg 8.135 mg
42ppm ~20 23-80 ng/mL 1.626 mg/kg 97.56 mg 24.39 mg
126ppm ~60 4.878 mg/kg 292.68 mg 73.17 mg
378ppm ~180 45 to 1800 ng/mL 14.634 mg/kg 878.04 mg 218 mg
Sirolimus
Dose
mg/kg/day
Dose
Blood/Sirolimus
Level
Male Median LS Increase Female Median LS Increase
4.7ppm āˆ¼2.24 3 to 4 ng/mL 3% 16%
14ppm ~6.67 9-16 ng/mL 13% 21%
42ppm ~20 23-80 ng/mL 23% 26%

Based on the FDA animal to human dosing conversion guide here.

Note: Ā½ life for sirolimus in mice is approx. 15 hours, vs. approx. 62 hours in humans. So, mice metabolize sirolimus approximately 4 times faster than humans.

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What is the sirolimus half-life in dogs?

I donā€™t know - Iā€™ll have to ask the dog researchers the next time I talk with them. Iā€™m assuming its somewhere between the monkeys (24 hours) and humans (62+ hours)ā€¦ but need to get the exact info.

Interesting. Even the low dose range per day converted for humans is higher than most people here take per week.

Yes, but these animals live in pathogen-free lab environments so you cannot expect the doses are reasonable for humans living ouside. Immune suppression is much less risky in the lab.

Just found this:

In a previous study utilizing rapamycin, a mean half-life of 38.7 hours was found by Larson et al. following a single dose of 0.1 mg/kg orally. This was far lower than the T1/2 of 99 hours observed following five consecutive 0.1 mg/kg oral doses in that same study.[51]. It should be noted that, similar to the variable T1/2 calculated amongst drug recipients in both previous canine rapamycin pharmacokinetic studies (oral and IM administration), our MRT was not consistent between recipients. While two of the four dogs had an estimated MRT within 0.2 hours (10.4 & 10.6 hrs), the MRT of the other two dogs was significantly less (3.1 & 1.3 hrs).[51, 52] Whether the MRT calculated in this study is due to the low rapamycin dose utilized, the intermittent dosing schedule, the duration of administration, or a combination of these factors, is unknown. Additionally, because none of our dogs had measurable levels of rapamycin in their blood after 48 hours (that is, at time zero in our study), this may indicate that our dosing regimen was more akin to intermittent pulse-therapy as opposed to a long-term, continuous treatment. At this time, the benefit or significance of this is unknown.

Source: https://www.biorxiv.org/content/10.1101/2021.01.20.427425v1.full

But also found this in my reading the literature, so donā€™t want to go any higher in dosing than Iā€™ve already goneā€¦ and probably not a good idea for the high dose I tried (1.5mg/kg), for longer periodsā€¦

Information regarding the use of rapamycin in dogs is limited. In dogs with experimental renal allografts, oral administration of rapamycin at a dose of 2 mg/kg resulted in severe toxicosis that was characterized by oral ulceration, anorexia, diarrhea, vasculitis, and death.13

Source: Pharmacokinetics of orally administered low-dose rapamycin in healthy dogs: A pilot study - PMC

And referenced: Rapamycin in experimental renal allografts in dogs and pigs - PubMed

Really wanted to find this paper: Rapamycin in experimental renal allografts in dogs and pigs - PubMed , but since its a 1990 paper, it seems to not be available online anywhere. The closest I could find was this patent by one of the authors of the aforementioned paper, on rapamycin for organ transplant rejection mitigation (see at bottom of this post), but this quote was interesting and notable (and very alarming, even if the dogs had renal transplantation prior to dosing):

Source below:

5212155_950.pdf (396.9 KB)

Interestingly, similar Gastro effects were seen (though this was just a dosing study, without the renal transplant) in dogs using Everolimusā€¦ not toxic (so the effects above seem likely more a result of the renal transplant than the rapamycin), but not very well tolerated. But with dosing up to 20 mg/ kg:

Source: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2010/021560s000pharmr.pdf

This is supposed a judgment free zone, butā€¦Iā€™m afraid I feel compelled to say something.

I am just going to voice once here that Iā€™m uncomfortable with the volunteering of pet dogs for self-research that seems far outside the norms for current research. Dogs in those more formal rapa studies are given precise doses, theyā€™re monitored by their vets (who are in on the study protocols), and their data is to be aggregated, standardized, and made available for further study/the greater good, etc. Theyā€™re approached as scientifically as possible for what they are.
There is absolutely no way I would deliver to my best dog friend high, daily doses of rapamycin based solely on things Iā€™ve read, unless i were both a veterinarian, and had a good understanding of how rapa works in dog bodies. Small doses, sure. But large ones, daily? Seems extreme and Iā€™m super uncomfortable with it. Iā€™m content to take my own health into my own hands, but risking my dogā€™s health by experimenting on him without his consent is a total non-starter for me.
If I wouldnā€™t do it to my own child, I wouldnā€™t do it to my dog.

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I appreciate your concern. And, of course we are all going to have different risk profiles when it comes to rapamycin and similar types of drugs. I tend to believe that rapamycin is an extremely safe drug, as its virtually impossible to overdose on - as this writeup suggests: Acute Sirolimus Overdose: A Multicenter Case Series - PMC

And I wouldnā€™t do anything regarding my dog that I wouldnā€™t do myself. This said, i definitely think that caution and research is highly advised when doing any type of experimentation. Iā€™ve been reading the research papers on rapamycin for the past 5 years, so I do have a little experience in the area.

But given the potential for vasculitis, I wouldnā€™t be trying a dose this high again anytime soon.

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I agree with ezb1970 about experimenting on your dog. Your dosages seem very very high! And you should at least be discerning from the effects itā€™s having on him, low energy, no interest in eating, that these dosages are very bad for him. Please pull back to the lower dose and save your dog! Some members of the raypeatforum.com are taking the rapa and one is giving it to her little old chihuahua with very good results at only 2mg. 2x a week. She herself is only taking 4mg once a week and is feeling great. That is as high a dosage as she is going to go. The members on the forum are experiencing very good results with their teeth and gums.

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