Define “therapeutic”? I am 57, I doubt any of these definitive answers will come in my lifetime.
My current n=1 philosophy is to push the outer range, without significant side effects or blood marker dysregulation, balanced against superior physical and cognitive capabilities.
I had one canker sore, and no noticeable side effects, or blood marker dysregulation as of yet.
Wild type mice only die of cancer…Rapamycin delays their death, but they still die of the same cancers.
How many people on this forum are doing advanced preventative cancer, CVD, or brain imaging scans as yet another reference marker?
But humans die of a great many other causes, CVD, cancer, neurodegenerative, diabetes and all the related organ complications.
With all my hacks, I am trying to address as many mortality pathways as possible…the goal should be to push out all cause mortality.
Assuming you’re taking Sirolimus tablets, your peak level blood draw may have been performed a couple hours early (see my previous post above), so your true peak level may in fact be higher than the result you got.
From the FDA drug insert for Rapamune tablets:
“After administration of Rapamune Tablets and a high-fat meal in 24 healthy volunteers, Cmax, tmax, and AUC showed increases of 65%, 32%, and 23%, respectively.”
Did anyone here attend the discussion with Matt Kaeberlein last week on the study, and was there any discussion around what we think we should be optimizing for in terms of dosing - Cmax, tmax, or AUC?
I think this is completely the right approach - we just need to be watching our bloodwork regularly (with a cost of about $70 per cycle its reasonable to do it every few months), and if things are fine there, and no bothersome side effects otherwise, slowly step it up.
I’ve found rapamycin to be surprisingly side effect free overall - I’ve taken doses as high as mid 30mg and really had no noticeable side effects (but need to track the blood work more closely).
Yes, I would love to hear Matt Kaeberlein’s thoughts on this topic.
In the ITP for the 42 PPM dose of sirolimus, male mice sirolimus blood concentration was 23 ng/mL (23% median lifespan extension, 8% max) & for females 80 ng/mL (26% median lifespan, 11% max)
Given that our personal weights are all different, I wonder if it might be helpful to also share our dosing protocols expressed as milligrams of sirolimus per kilogram (mg/kg).
Rapamycin was approved in 2006, and has been used safely for almost 20 yrs. There is even a small study paper on “acute Sirolimus overdose” cases, all without any serious permanent effects.
If we look at the GFJ/Ketoconazole/Rapamycin study side effects, in the Sirolimus alone or Sirolimus/GFJ combination, the DLT (dose limiting toxicities) are 20mg+ MIN. Most all of us are taking MUCH less than 20 mg/week.
With regular tracking of biomarkers, I think it’s relatively safe (my personal opinion, I am NOT a doctor, this is NOT medical advice) to explore pushing the envelope of weekly dose, everyone an n=1. I am under the care of a doctor in my journey.
I’ve extracted the side effects tables from the paper.
I dug into the supplementary tables for some additional insight.
They did not publish the specific ages of the population, other than 27-82 yo. A good mix of male vs. female. There was no commentary in the paper about pharmacokinetics and age (in case the doctors decided to try different dose by age), nor by sex, unlike many mice studies where there are major differences between sex. But the by-age dose targeting may have been severely confounded by cohort demographics, namely every person in this study had advanced malignancies cancer, mediating their dosing over any age consideration. Similar to other pharmacokinetic papers, there is a wide variation in response between persons.
The 2nd table shows the large variation inter-person, and between dosing levels, in change in Cmax and change in AUC over base Sirolimus alone, highlighting the unique n=1 response. My highlighting of SD In red.
Since I don’t see much, if any, trend in the “fold change” as the dosing levels change, I assume any correlation between fold-change and dosing levels is being swamped by interpersonal variation.
So, for me, at 5mg with GF and the resulting Cmax=17ng/mL, I am falling within a standard deviation of their GFJ at 15mg (Cmax and SD multiplied by 1/3 to 26 ± 18 to account for my lower dose).
Also, remember the grapefruit juice used in those studies was a special GF juice provided by the state of Florida researchers that specifically had high levels of the active ingredients that maximally inhibit CYP3A4. We have no idea how much of those active compounds are in standard store-bought GF juice and/or how much they vary from batch to batch, seasonally and/or between brands.
Most all of the pharmacokinetic studies I’ve read showed significant inter-person variability. Our individual n=1 responses are very complex, leading to intrinsic and fundamental differences in absorption between us, not explained in study replicability/reproducibility.
There are polymorphisms in the intestinal and liver enzymes, including CYP3A4, and others (CYP3A5, CYP2C8, and CYP2C19). There are polymorphisms in the mTOR genes! We all have different gastro/intestinal functionality.
Therefore, if we’re trying to reach certain Cmax/AUC/trough targets, we need to each do our own pharmacokinetic experimentation.
You could take an alternate, blast away approach, starting with high dose, and then dialing back when you reach discomfort/toxicity thresholds. Based on previous studies, these DLT (dose limiting toxicities) markers are noticeable, measurable & reversible.
Here are just a few references of polymorphism effects on pharmacokinetics.
Let’s not forget the variability in the Sirolimus in the pills you get. Since that is the first number in all these calculations it has a profound effect on all the number crunching that follows. Given the host of generic sources and the know problems in quality/quantity, a 1 mg pill could be 1 mg or maybe 0.5…or maybe 0.0.
Testing is expensive but could we set up a system where we join to have a system to share cost of testing across a variety of “preferred” vendors who we use and have good service and price. Publish that. Then do this again in 2 months (or on some continuing basis) so we have validated vendors. Not simple but given all the effort in trying to get to the best dose and other costs involved it seems worthwhile. That is my biggest question in rapamycin dosing…what’s in the pill.
Or maybe MK could share his testing results and the vendor and we can use that.
You are not questioning the quality of the Sirolimus in these clinical studies? They are using Pharma grade product, so this is NOT a variable in theses studies. So the inter-person variability is fact beyond the drug.
Now I do agree with you that for those of us sourcing generic product from all over the world, then yes, this adds yet another variable. You’d have to have to analyze every batch you receive, and even then, what is the variability/purity within the sample.
Not questioning the quality of the message used in the studies. That is not the point. The point is the quality of the product we buy for our use. Was just a thought in case they did buy from some traditional vendors. Someone on here wrote that was the plan for the big dog study. IDK. Doesn’t hurt to ask…it is in KB and other Rapa boosters interest to help get good, potent product into the market.
As for testing the generics we buy from India, there are 4-5 main sources. Yes I do realize there are 100’s of sellers but easy to narrow down to a few…one who have a reputation with people here. Thats a detail to be worked out and can be done. And they have a brand or two each. So with pooled resources testing 10 samples is not that big a deal. True, one batch could be fine and a month later not good…but you have to start someplace. I’d sure rather buy a tested "good’ brand to start then one with poor content. And follow up testing over several months establishes the vendors with consistently good product.
Intrabatch variability is possible but much less a concern than very low quantity in entire batches…that would be a manufacturing defect not just cutting the amount of product in everything. So you deal with the worst problem first.
And maybe we find its all up to snuff. So one variable sorted out.
