Concerns on improving Cmax and plasma halflife

Hi there,

Is there a way to get some hints that raising Cmax and plasma halflife is positive for longevity purposes?

I have read about improving Rapa’s bioavailability with, for example Ombitasvir+Paritaprevir+Ritonavir, and, that that will increase Cmax, AUCinf and, plasma halflife.
So what is the thing that causes the benefits for health and lifespan? Is it the elevated blood levels of sirolimus once a week and Cmax is totally that thing?
Or do we want a continous plasmalevel?

The dose regime for organ transplantation patients is daily up to 4mg sirolimus. In that case, they have moderate Cmax peaks and a continous blood level.
For longevity purposes most people take a relatively high dose once a week. Here we have a decreasing but also permanently present blood level of sirolimus but with a much higher peak in Cmax than in organ transplant patients.

So I am a bit suspicious if bioavailability improving medicines will be a good thing for us. In case of GFJ, we only improve the Cmax. In case of Ritonavir we also increase the plasma halflife which might, from my point of view, be detrimental.

Any ideas?


Effect of a ritonavir‐containing regimen on the pharmacokinetics of sirolimus or everolimus in healthy adult subjects

Following co‐administration with the 3D regimen, the everolimus Cmax and AUCinf increased to 4.7‐fold and 27‐fold, respectively.

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For cost savings, I take 100 mg of Ritonavir 3 hours before taking 1mg of Rapa/Sirolimus. Once weekly.

So, in theory 100mg of Ritonavir is supposed to deactivate most of CYP3A4. That should boost the 1mg Rapa dose to effectively ~5 mg.

CYP3A4 is regenerated within 2-3 days. This means the half life of Rapamycin is only increased for 1-2 days.

The plasma concentration curve of Rapamycin should theoretically be similar to taking 5mg on day one and ~2mg on day two. However, it is not clear to me how much CYP3A4 is deactivated by a single Ritonavir dose, and how fast it is actually regenerated.

I suppose it would be a good idea to measure blood levels of Rapamycin at day one, day two and day three to actually validate the dosing scheme.

Does anyone else use Ritonavir to boost Rapamycin? How do you do it and why?

I am thinking of doing it. I have Ritonavir available. Did some research, below are two papers that seem to help making decisions on dosing an timing.

Brit J Clinical Pharma - 2015 - Greenblatt - Ritonavir is the best alternative to ketoconazole as an index inhibitor of.pdf (777.8 KB)
eichbaum2013.pdf (279.2 KB)

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Im taking ritonavir & rapa since a year or so and read some papers before.
I found out that 2mg ritonavir & 2mg rapa works best according to the papers.

Side note: In PAXLOVID they are also using 2mg ritonavir just because of the CYP3A4/5 inhibition.

My conclusion was:
as I could not know for sure which CYP3A is my active one, I choose ritonavir instead of ketokonazole (and because ketoconazole is only available as a shampoo here).

If your conclussion, dosing regime and so on is any different to mine, please let me know. :slight_smile:

my wife, my mother and I are using the same dosing regime without adverse effects. Just if you have any concerns about ritonavir. Dosing regime is: 2mg rapa/2mg ritonavir every other week (maybe every 10 days will also be okay, but every other week is better just because I cant make sure that my rapa level will drop below the curve after 10 days).

BTW: I havn’t found a physician who can test my rapa blood levels. intresstingly, they can test me for everolimus, but not for sirolimus. If you have got any ideas which laboratory is testing for rapa, please let me also know. :slight_smile:

200mg according to the papers. If you’re taking 100mg, you can’t make sure that you get 5.5mg.
If using rapamune you could propably add 33% bioavailability, but AFAIK there are no papers ou there testing rapamune + ritonavir for the bioavailability. So we can’t make sure it is a real effect.

assume 3 days to be safe, CAP3A4 needs 3 days to be fully regenerated.

See my previous posting. But yes, we can’t be absolutly sure about that

despite that, my blood markers improved while using my dosing regime. I’ve tested i.e. my complete blood count (and some more).

Transplant hospitals usually test it, so search for a transplant hospital near you and ask. Oncology hospital is another option. Usually it is done in radiochemical labs (CMIA method).


Thank for these papers. Eichbaum arranged single Ritonavir doses 10 minutes before Midazolam.

But given the more irreversible kind of CYP3A4 inhibition by Ritonavir, I’d say it’s better to wait some hours (especially if taken after a meal) so that the whole Ritonavir dose is completely resorbed and had some time to deactivate most of CYP3A4.

In theory, it is correct that additional or larger doses of Ritonavir might provide a slightly bigger CYP inhibition and thus slightly (?) higher Rapamycin levels. But it’s very hard to analyse the actual difference that - e.g. - 200mg vs 100mg once vs 2x 100mg Ritonavir make.

Are there clear recommendations for Sirolimus/Rapamycin blood levels for anti-ageing that help to analyze if my levels are within recommended range?

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I usually take rapamycin on empty stomach, so I guess if I decide to add Ritonavir, 30-60 minutes would be plenty.
I wouldn’t go more than 100mg, seems from the study that 100mg would give around 90% and 200mg maybe slightly more, but it doesn’t make sense.
Ritonavir in single dose should give a slightly extended half life curve, I wanted to measure my blood levels but never have the time to do it. I wanted to test without and with Ritonavir and compare.
Since you and @Qurestine are both using Ritonavir maybe I will have more courage to try.
I wanted to try 2mg Rapamune with 100mg Ritonavir in weekly schedule. I am at the moment trying daily 1mg for two weeks and one week off with greater benefits in my wellbeing, much reduced fibromyalgic pain, much improvement in seborrheic dermatitis and some immune response improvements. Last two weeks there was a COVID19 outbreak where I work, all my colleagues got sick and I did not and my last contact was more than an hour long conversation in a not ventilated small office with someone presenting all symptoms. So I gathered it must have been some protective effect from rapamycin.
There are no established blood levels for longevity, but from this forum I concluded that medium doses from 6-10 mg weekly offer most benefits.

Yes, in a general sense, we can see that higher dosing (within the range tested in mice so far) the higher the dose, the greater the longevity effects. But this was for mice in sterile, pathogen-free environments (lab environments). Unfortunately we don’t live in that type of environment. The mice are highly immune compromised at these high levels, and would likely suffer/die in a regular environment with the typical infectious agent exposures. There have been situations where people are taking high daily dosing of rapamycin / rapalog (everolimus) … for example 10mg/day in some trials, and at least one young woman got sepsis and died… see details here: Rapamycin Taken with GFJ and EVOO - #11 by RapAdmin

And - while think the general belief is that its the AUC (area under the curve) of the exposure to rapamycin that matters (vs. the CMAX or half-life), I don’t think I’ve seen any research on this issue specifically with regard to lifespan - so I think we don’t know for sure of the impact of each of these variables independently on lifespan.

Here are the dose translations (and LS (lifespan) increase) from the other rapamycin studies:

Dose for 60kg Human Daily Dose adjusted for longer half-life (/4)
4.7ppm ∼2.24 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
Male Median LS Increase Female Median LS Increase
4.7ppm ∼2.24 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: ½ 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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@RapAdmin I wonder about this statement. I think it is a central question that drives our experiment. I’ve also heard that the peak is the target instead of the AUC. If AUC was the target why not take 1-2mg per day for a week and then clear it to avoid mTORC 2 impacts. I’ve been convinced that the primary target is to reclaim the mTOR flexibility lost to aging (hypergrowth). So hit (turn down) mTORC1 hard but fast and short, then let it recover. Then do it again and again until it gets rebalanced. This argues for high peak, then clear it fast. No fat with rapa to slow absorption. If you get immune system side effects you are doing something wrong.

What am I missing?

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There is really no consensus on that even among researchers. The current human pulsed dosing is based on avoiding mTORC2 suppression, but rapamycin does not suppress mTORC2 directly and doses at which it would be suppressed detrimentally are almost unattainable in humans. (I posted studies on this elsewhere on the forum)
With high peak you risk rebound effect, your mTORC1 accelerating even faster to catch up and you end up with mTORC1 signaling above baseline.
If the hyperfunction theory of aging is correct in this case it would make much more sense to suppress unnecessary and persistently activated mTOR all the time. To slow it down, decrease the function to optimal function. The only problem is that nobody knows what is the optimal function or how to measure the optimal function.
I am currently experimenting with unorthodox daily dosing schedule with great success. I got an idea from Pankaj Kapahi’s experimenting with his daily dosing. I take 1mg ED for two weeks and I take one week off and I repeat. At the moment most observations are not measurable, I am getting blood tests done in few weeks, but so far my experiment N=1 is doing well.


Thanks. That’s a sensible approach if mtor is broken and must be semi-continuously pushed down to slow aging. That might be right.

I’m working under the assumption that I want cycles of up/down mtor. I’m trying to create cycles of growth and retrenchment using cycles of rapa and protein consumption and other nutrients. If I can get my immune system to work better for repairing my body, then I’m slowing aging and possibly clawing back some aging. And, of course mtor isn’t the only game in town for improving the immune system.

Yes, but mTOR is not an on/off switch. It is more like a volume button, you turn it up and down. Even when is down it is still on.
Another reason for high peaks was tissue penetration, especially BBB but it might not be necessary as many drugs have peripheral effect that somehow leads to physiological changes in the brain.


I’m sure you’re avare of it but … CYP3A4 needs 3 Days to rebuild completely. So in theory your rapa blood levels will never fall under the curve. BTW intressting to know that rapa helps with your fibromyalgic.

As ever, you’re a quit good source of knowledge. Thanks!
But what’s with the lifespan increase at 126ppm and 378ppm? Did the labratory mice outlived their staff so it was no one there to collect the data? :wink:

Sadly the highest doses were in a transient, short term dosing protocol so we don’t know the full life extension effects if they would have kept it going for the mice’s full life.

Here is that study…


Yes, but I am trying now a schedule that is two weeks daily 1 mg and one week off. Maybe I will try 2 mg + 100mg Ritonavir for three weeks and one week off… As far as I understand and have researched rapamycin I have no problems with continuous blood levels, on the contrary. If no adverse side effects of course. So monitoring CBC will be a priority and measuring rapamycin blood levels one week to be able to predict the curve.

Interesstingly the female lifespan decreased in the transient treatment.

This could mean anything. BL6-Mice are genetically homogeneous and bred to develop cancer.
They should do the experiment again with wild type mice.

Yes - I think they also speculated that they may have reached the maximum beneficial dosing for rapamycin in female mice, with this trial.

They have also reported that in mice at least, females seem to process rapamycin differently and that the blood levels (for the same dosing) were three times higher in female mice vs. male mice. I don’t think we’ve seen the same difference in human males and females.