I tried rapa weekly for a short period and wasn’t happy with the experience. Among other things, I had a change, including bleeding, in a stable mole I’ve had since I was a teenager. It turned out to be early stage squamous cell carcinoma which was easily removed. Still, it was the first cancerous mole a have had develop in my life.
After that, I laid off of rapa for several months but just initiated a 5 mg. dose a few days ago. I’m thinking of trying a monthly interval and wonder if anyone has thoughts about how much potential benefit is lost for someone in his late 70’s or other potential issues.
After some experimentation with dose/frequency, I am now taking 3 mg every three weeks. My “dose limiting toxicity” was always aphthous ulcerations, which are highly annoying. I started with 1 mg/week.
One of the issues to be worked out with rapamycin is whether the benefits and/or the toxicity are related to the maximum concentration after dose (so-called Cmax) or are related to exposure. By exposure, I mean the integrated concentration over time curve (technical term is AUC - area under curve).
So this results in various scenarios - pulse dosing with enough time to get back to a zero blood concentration, or daily dosing to reach a more even exposure, and everything in between. All these scenarios likely have their risks/benefits but we still need more data. Reading the literature, I think there is some benefit to pulse dosing, and I suspect it may have a good risk/benefit but this is a conjecture.
I will see what happens if I increase my dose to ~8-10 mg/three weeks over the next year or so. Some factors I have taken into account are that with a terminal T1/2 of ~67 hours, dosing weekly may result in some accumulation since a week is only 2.5 half-lives the old rule of thumb being 5 half lives to zero. If I get toxicity, I may decide to go for monthly intervals, aiming for a high Cmax.
This is just my opinion, while some on this forum have been thinking about these issues much longer than I so I would scan the rapamycin focused topics for good information and personal observations and experiences.
In the past, l have tried 8 mg weekly and then every 2 weeks for a total of 4 months. During that time, my healing rate slowed noticeably and l got sick at a much higher frequency. I’m currently doing 4 mg every 3 weeks(only 5 weeks in). My theory is l am slow metabolizer, assuming 85 hour half life and shooting for 5.5 half lives.
At the end of 4 months, just prior to the time where you would have taken the next dose of 8 mg (with 15% bioavailability and biweekly dosing), approximately 1.284 mg of the drug would be present in your body just prior to the next dose. (85 hour half-life)
At the end of the same 4 month period with dosing 4 mg every three weeks, 15% bioavailability, same half-life, at the end of 4 months, just prior to the time where the next dose of 4 mg would be given (with 15% bioavailability), approximately 0.610 mg of the drug would have accumulated in the body.
Congratulations! You came up with a dosing regimen that leaves almost exactly 50% of the drug in your body before the next dose of drug compared to the previous dosing regimen. I hope that works out for you abolishing the toxicity you noticed.
I went through a similar routine to arrive at my current dose of 3 mg every three weeks, assuming a half-life of 67 hours and 15% bioavailability. Of course, the assumptions for the PK equations are a particular half-life and a particular % bioavailability.
Actually you followed the math better than I since I calculated the amount in the body after, not before the nth dose at steady state. So the accumulation is 0.084 mg and 0.010 mg respectively present before the next dose and 1.284 mg and 0.610 mg right after the next dose.
@Herm and I are I think the only two people on this forum who have gone for dosing every 21 days.
What I think really matters, however, is not the level of rapamycin when the next dose is taken, but the proportion of time that rapamycin is too low to have a material effect.
I take a higher dose of 6mg (Zydus or Biocon) with pomegranate, pomelo or grapefruit.
@John_Hemming I agree, based on my interpretation of the animal literature. I would posit that benefits accrue proportional to the Cmax, the highest concentration that occurs after oral dosing, while the adverse events are related to the amount of time the blood concentration remains above some undefined concentration, with a lot of individual variance. Compounds found in GFJ, discussed in this forum, increase AUC (exposure) 350% implying up to a 3.5 x increase in half-life, which is quite a lot. If you started with a 67 hour half-life, now it would be 234.5 hours, which is a little over a week of 168 hours, hence the accumulation. Quadruple checked the math thanks to @KarlT and this implies 1.75 mg of rapamycin are in the body before the next dose if 6 mg were absorbed and 0.163 mg if 15 % was absorbed. Actually you may absorb even more given decrease of rapamycin clearance as GFJ inhibits intestinal CYP3A4.
Can you guys who have been taking and experimenting with rapa longer identify the ideal blood level profile? Is it to achieve the highest Cmax (if so, how high) followed by the shortest (or the longest) right tail? And how is this goal modulated by GFJ and other CYP3A4 inhibitors? If I understand GFJ correctly, it seems like a free lunch in that it increases Cmax and lengthens the tail of decline, if that is the goal). Quercetin seems to have a different impact.
Practically speaking, I have been under the impression that I wanted to do a little “house cleaning” and then return my immune system to its former state as quickly as possible. I spend a lot of time in the sun, for example, and do not want to have to avoid it for days on end. This last week, I took 4 mg. with sardines and no CYP3A4 inhibitors other than the fact that a small amount of quercetin is part of my daily supplement stack. I don’t know if this is a good or bad strategy because I’m unclear on the agreed upon goal, other things being equal.
I’m currently doing 3mg every 21 days/3 weeks as well. It seems the the sweet spot for maintaining the benefits and works well around my time spent in high risk of infection exposure on the job.
Restating the question, is it better to have more constant but lower blood levels, or pulse dosing to achieve beneficial effects? And how does this change the adverse event profile? As an example, 1mg/day. or a pulse dose of 7 mg / week. Both of these doses result in the same exposure. If anyone knows of a comparative study, even a short one looking at some surrogate biomarkers of inflammation and related to an"on target" effect of rapamycin I would be interested in hearing about them. At this point, I don’t think we know which dose regimen gives the best risk to benefit. So I digress to biochemical philosophy.
Mark Mattson has done some amazing work in the nutritional impact of diet on ageing. One concept which has intrigued mefor a long time is the concept of [hormesis] (https://journals.sagepub.com/doi/pdf/10.1177/0960327107083417) that is, beneficial effects of low levels of stress. Caloric restriction is a form of cellular stress. Rapamycin has effects that biochemically mimic caloric restriction. Fasting has beneficial effects, but obviously at some point, you have to eat to survive. So my hypothesis is that pulse dosing with rapamycin, a mimic of fasting over the period of time when blood levels are higher than some unknown concentration may also confer similar benefits, but also allow between dose recovery back to a homeostatic state. A dosing regimen that maintains the blood level above that unknown concentration over the dosing period, weeks, months, etc. may not be as beneficial, much like fasting over a very long period of time. Decreased protein synthesis, increased protein catabolism, changes in lipid metabolism, immune effects, etc.common to both long term fasting and continuous rapamycin exposure. But it is just a hypothesis, but one on which I will take a gamble until I become aware of more data.
Regarding GFJ and friends, the phytochemicals present decrease intestinal and liver CYP3A4 thereby increasing the fraction of dose absorbed, and decrease clearance thereby increasing half life. The increase in fraction absorbed is frugal as it is analogous to taking more rapamycin which is more expensive than GFJ,but the decrease in clearance and extension of half-life may or may not be beneficial depending on how much the clearance decreases (or half life increases). For me it would be nice to have a compound that increases fraction absorbed, decreasing the adverse events to the wallet and bank account, but has much less effect on total clearance, but such is not been found as far as I know.