#10

Your method may get useful data, but that is not how half life is measured.

#11

It’s a big impact on how often we can take rapamycin without side effects, if Matt’s data is correct. It’s natural we hope he can be very sure.

Probably our weekly dose are too modest to really have an efficacy on delaying aging?

#12

No this is all consistent. Single doses of rapa average around 35 hrs … daily dosing is in the 60s. As we get bigger single doses they start metabolizing a bit more daily dosing.
The comment on Dr not being a kidney transplant patient isn’t relevant, this is not renal metabolized, it is primarily hepatic metabolism.

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#13

You can absolutely see 2 serial levels and note the interval between those and estimate half life. There are drugs that have zero order metabolism where that isn’t the method, but that was certainly the teaching when I did my graduate pharmacology courses. I’m happy to learn if you are a specialist in drug metabolism and have a critique.

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#14

@Agetron has been good at doing measurements - any comments?

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#15

@Stijn do you have a color to offer as an expert at testing rapa blood levels

For others, see context here:

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#16

Matt Kaeberlein didn’t say whether or not he exercised during that period.

Since rapamycin and exercise are at odds with each other, would exercising the next day shorten the half-life of rapaycin?

We also don’t know what supplements he was taking the day of rapamycin or the day after.

"Creatine Supplementation: Creatine supplementation has been found to amplify the resistance exercise-induced decrease in serum myostatin, potentially by activating mTORC1 and increasing insulin-like growth factor-I (IGF-I) activity at rest’

"Resistance exercise can potentially affect medication half-life through the following mechanisms:

  1. Increased Blood Flow and Metabolism
    During resistance exercise, there is an increase in blood flow to the muscles and other tissues. This increased blood flow can potentially enhance the delivery of the medication to its target sites, leading to faster absorption and distribution. Additionally, the increased metabolic rate during exercise may accelerate the metabolism and elimination of certain drugs, potentially shortening their half-life.

  2. Changes in Protein Binding
    Exercise can cause changes in plasma protein levels, which may affect the binding of drugs to these proteins. If a drug is highly bound to plasma proteins, changes in protein levels could alter its distribution and elimination, potentially affecting its half-life."

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#17

In the study below, “Healthy volunteers were administered a 15 mg single dose of sirolimus on two occasions, once while fasting and once after consumption of a high-fat breakfast.”

Despite the fact that the breakfast increased absorption by 35%, there was no difference in the terminal half-life, which was an average of 67 to 68 hours.

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#18

The point isn’t to sort out why his half life is 8 hrs. The point is he has made a fundamental error and his half life isn’t 8 hrs.

So one of my pts takes 9 mg w GFJ and at 20 hrs has a level of 7.2. I get a level 48 hrs later and it is 3.4. So if it were 3.6 then his half life would be 48 hr as half of the drug would be gone. In his situation slightly more than half was metabolized… so it would be roughly 43 hrs give or take.

So if I’m concerned about time someone is over 3.0 I would know that he will be north of this for at least 85 hrs give or take … with that dose.

So then for dosing interval … I’m going to want it about 3 times that 85 hrs.

I’m not formally doing the math, but these are close.

It’s important to note a lot can be done in absorption and if taking GFJ seems more on absorption than rate of metabolism at least on just taking 2 doses of GFJ 12 hrs apart.

But exercising and most other things will make very little difference.

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#19

The half life was established in kidney transplant patients from what I have read. These patients are obviously not in the best health, take other medications, and I believe it is common for them to have hepatic impairment. Half life, as you know, has many variabilities from patient to patient.

#20

Sure, the half life can be extrapolated as you say and in some ways be more useful. However, Matt Kaeberlein’s method was pretty close to what the AMA and NIH recommend.

#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.

IMG_0120
IMG_01201920×1088 115 KB

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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.

1600×903 137 KB

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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