#21

In the study below, healthy men were given single doses of rapamycin as low as 1 mg/m^2, and as high as 8 mg/m^2 with half-life measures. About 2 to 16 mg as a single dose.

Men given the lower dose of about 2 mg had a mean rapamycin terminal half-life of 69.7 hours (whole blood). Men given the higher dose of about 16 mg had a mean rapamycin terminal half-life of 86.4 hours.

Also tested were 3 and 5 mg/m^2.

So it’s definitely not consistent with published empirical data. You can see the distribution below.

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#22

My experience with healthy patients taking Rapamycin confirms exactly the same range of T1/2 reported. The fact someone has a transplant doesn’t result in any significant differences and I’ve seen this in enough patients to simply say the range in T1/2 is in the 30’s-40’s on single doses. So I have real life experience and data - and I know that an 8 hr half life the rationale behind reporting it that way is simply a reflection of a basic misunderstanding that one can start the metabolism T1/2 calculation with measuring the peak level after initial absorption. An amateur error - but there is no reason why he would know that. He isn’t a PharmD or a physician who did graduate pharmacology training. I am.

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#23

This is precisely the reason why I measure and check this and make sure my patients take the meds exactly the same way each time with the same food or with/without GFJ or Pomegranate Juice … so we can understand their metabolism. However, there is not situation in which someone has a T1/2 of 8 hours – it is a knowledge deficit as detailed above.

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#24

I definitely don’t mind doing a trough after like 7 to 8 days, just to make sure that my rapa level is below one ng/mL… and then I like to take my dose 2 pills of 2 mg… 4mg total with fresh red grapefruit juice. Do a second blood measurement and I usually I get a multiplication of about 3. Measurement at 2 1/2 hours after the dose. … been getting in the area of about 22 ng/mL. That’s the equivalent of 8 mg with no grapefruit juice.

Only interested in seeing what my c max is after 2 1/2 hours, not really interested in 8 hours later… plus it’s inconvenient for my lab draws with my physician.

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#25

I am not medically trained but I can read the papers.

Why do you ignore the genetic or age factors?

Because Matt Kaebelein is much younger than most of Doctor Greene’s patients, I expect him to have a faster clearance rate. There is also a possible genetic factor.

Also, you must recognize drug interactions.

Not enough data points to make anything but a rough guess based on half-life calculations, but it certainly looks to me that rapamycin has a half-life in Matt Kaeberlein of between 7 and 10 hours.
I am not medically trained but I can read the papers.

Why do you ignore the genetic or age factors?

Because Matt Kaebelein is much younger than most of Doctor Greene’s patients, I expect him to have a faster clearance rate. There is also a possible genetic factor.

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Also, you must recognize drug interactions.

Not enough data points to make anything but a rough guess based on half-life calculations, but it certainly looks to me that rapamycin has a half-life in Matt Kaeberlein of between 7 and 10 hours.

Unless there is repeated testing with the variables reasonably controlled, no one knows what his/her particular half-life metabolism is.

A quick survey of the various things that can affect a drug’s absorption.

Diet, exercise, supplements, other drugs, fasting, genes, etc., show that the

half-life of rapamycin in any individual must be tested. Unless all variables are kept the same repeated testing would show different results.

I must interject that I think, from experience, electrical/electronic testing is much easier than medical testing because we normally can control all of the variables"

This is one of the reasons so many medical papers are junk. They can’t or will not control the variables.

Bottom line: You can not possibly know the half-life of rapamycin in any individual without repeated testing while maintaining control of the variables. Anything else is just an educated guess at best.

“volume of distribution, and half-life are used in drug regimen design, the genetically introduced variability in PK, specifically CL, can influence the drug maintenance dosing regimen. This variability related to clearance and the influence on maintenance dose design will be discussed in some detail below.”

See the table: Table 1

Examples of the Influence of Variant CYP450 Alleles on the Clearance and Maintenance Dose of Specific Drugs

“Genetic variations in drug-metabolizing enzymes and transporters can significantly impact the half-life of drugs”

(1) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159057/

The Impact of Diet and Exercise on Drug Responses

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304791/

“Effect of Aging on Metabolism and Elimination of Some Drugs), clearance typically decreases 30 to 40%.”

https://www.merckmanuals.com/professional/geriatrics/drug-therapy-in-older-adults/pharmacokinetics-in-older-adults

Unless there is repeated testing with the variables reasonably controlled, no one knows what his/her particular half-life metabolism is.

A quick survey of the various things that can affect a drug’s absorption.
Diet, exercise, supplements, other drugs, fasting, genes, etc., show that the
half-life of rapamycin in any individual must be tested. Unless all variables are kept the same repeated testing would show different results.

I must interject that I think, from experience, electrical/electronic testing is much easier than medical testing because we normally can control all of the variables"
This is one of the reasons so many medical papers are junk. They can’t or will not control the variables.

Bottom line: You can not possibly know the half-life of rapamycin in any individual without repeated testing while maintaining control of the variables. Anything else is just an educated guess at best.

“volume of distribution, and half-life are used in drug regimen design, the genetically introduced variability in PK, specifically CL, can influence the drug maintenance dosing regimen. This variability related to clearance and the influence on maintenance dose design will be discussed in some detail below.”

See the table: Table 1
Examples of the Influence of Variant CYP450 Alleles on the Clearance and Maintenance Dose of Specific Drugs

“Genetic variations in drug-metabolizing enzymes and transporters can significantly impact the half-life of drugs”

(1) https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4159057/

The Impact of Diet and Exercise on Drug Responses
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8304791/

“Effect of Aging on Metabolism and Elimination of Some Drugs), clearance typically decreases 30 to 40%.”
https://www.merckmanuals.com/professional/geriatrics/drug-therapy-in-older-adults/pharmacokinetics-in-older-adults

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#26

This simply confirms that you are taking real rapamycin, and shows a higher level than you’d get without GFJ. If however, you want to look at your personal T1/2, you’d need to get a later level, and then a second level. If you are only interested in Tmax … sure … do this, I however, would think it more useful, even if not looking at T1/2 to understand what effective level you achieved, which really would be more in the range of looking at levels at least 4-6 hours out from taking the medication.
The real level is that which represents both absorption and distribution … not just absorption - it isn’t until you understand that, that you can start looking at the metabolism, as it is the distributed drug that is the basis of metabolic T1/2, not a peak level in many such drugs.

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#27

Sadly just isn’t the case - I can’t share patient data – but I’ve not seen any pattern with age - I have patients a lot younger and at least as healthy as Dr. K who have T1/2 all in the expected range. It simply isn’t the case. His T1/2 will be 30-40’s for a single dose. He made a mistake in his approach.

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#28

OK, I re-watched the video and I do agree some errors were made. If my calculations are correct, the half life he is getting is around 17 hours, using the 13.8 and 2.9 level after 20 hours…
T1/2 = (.7 X 13.8) / .545 = 17.7 hours

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#29

I would suggest that if he simply did my protocol of a level at 20 hrs then 48 hours from then … you’d see a T1/2 in the expected range. Getting a level way down the line e.g. almost 72 hours after dosing really gives a much better idea of how much of it is still around. Without that data, you have no idea. I have this data on a dozen people who are healthy … and I can simply say that 8 hrs or 17 hrs isn’t going to be correct. Now, give me another year in this space and I’ll have much more confidence - but I have the data on a dozen people, and this simply is so dramatically different, but also not measured in a sensible fashion - that I’d simply not draw conclusions without a sensible approach to measuring his levels that eliminates the redistribution part of this.

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#30

@DrFraser Thank you for all of your intelligent posts on this matter. I was going to chime in and give a similar opinion to yours, but you’ve covered all the bases better than I ever could. It’s a pleasure having you here.

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#31

OK, thanks for explaining some of this. You have made some valid points.

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#32

Excellent post. I was doing some reading on the NIH, and you have gathered some great information for anyone interested in the half life of medications.

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#33

@Agetron i thought you used to get much bigger rapa multiplication effects than 3X. Did that change due to lower dosing or a different protocol…or do I miss remember?

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#34

If you don’t understand why this is bothersome then you’re not a scientist and you’re on the wrong part of the Dunning Kruger curve.
Any scientist who does an experiment and gets results that are 8 fold different should be shocked, would assume he did something wrong, and repeat the experiment.

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#35

I think you are projecting and it is not an experiment.

#36

I completely understand your point. But going on 3.8 years I am looking at max dose and its clearance from my system. What hapoens in the middle is the catabolic process.

I have no interest in taking more - made that mistake for 7 months… with 6 -8 mg with GFJ and had 36 -40 ng/mL . Almost double my current dose, and trashed my biological gains in inflammation and methylation.

Although biological tests are sometimes negated by Attia, Kaeberline and others, I do feel that Glychenage blood measurement of inflammation is a very good biological marker. Along with TruMe methylation spit test, they consistently run parallel as 2 very different tests, measuring 2 very different things. In me.

About to retest both and I am curious about the pattern. If continued positive biological numbers are found, it will solidify my dosage plan.

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#37

@Agetron Let us know how your tests go! Hopefully you have gotten even younger! :slight_smile:

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#38

Hey Joseph,
When I took 4 mg of the with red grapefruit juice and got a measurement of 22 ng/mL. I was thinking that was an increase of almost 6x’s .

What changed my perspective is that 8mg of rapamycin gives Matt Kaeberlein an 20 ng/mL. So ng and mg not the same.

So my dose is closer to a 3x’s increase.

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#39

3X is what we would expect. So, it’s right on target with expectations.

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#40

I think DrFraser is correct and Matt is confusing distribution half-life with terminal half-life, and making conjectures with not enough data in the terminal phase. I’m going to make a conjecture with the sparse data anyway to illustrate the point. Looking at the video graph at 12:45, and due to the sparse sampling using two data points, with the last data point assumed to be zero, the question is how long does it take to go from 2.9 to 1.45 ng/mL? Very roughly it looks like ~100 hours. So the terminal half life would be around 100-24 = 76 hours. That’s a bit high and another conjecture is that the zero point probably occurred earlier and a detectable level/time point towards the end of the curve is missed. That would “shorten” the estimated half-life, but likely not down to 8 hours! Rapamycin kinetics in dogs](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642271/) is well described by a two compartment model, with a first-order oral absorption The first half-life, that is sometimes called the “distributional half-life” is relatively quick, where the drug is moving from blood to elsewhere in the body from blood, but once that dynamic shift has taken place the terminal half-life better reflects clearance of the drug from the body. Having a data point at 72 hours or even better 48hr and 72 hr and 96 hr would have been much more informative.

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