Introduction // Ritonavir for rapamycin-boosting

First of all, I would like to introduce myself:
I’ve been following the forum for quite a long time now, generally the discussions here seem good and well thought out, as does the administration.
Time to register and briefly introduce myself. I am an acute care physician (3 board certified in critical care, emergency medicine and general medicine). Perhaps also because of a certain exhaustion in caring for very sick people (who usually have not invested so much in prevention :slight_smile: ) I am interested in the longevity field.
The possible effects of various interventions (drugs such as rapamycin/metformin etc., exercise, CR etc.) are extremely interesting, but of course we have to admit that our knowledge is very limited and, despite all our enthusiasm, we must remain critical. In this respect, I look forward to the discussions here…

Now a first question for the group
Since the cost of sirolimus here in Europe is rather high:
has anyone had experience with ritonavir to boost, i.e. sirolimus peak levels with and without taking ritonavir (Cmax, AUC is then another unknown)?
I have only found this publication
, but it assumes a continuous intake of ritonavir, I would have rather thought of a 12h intake before and with sirolimus.
Grapefruit juice is certainly also an option, but its effectiveness may fluctuate depending on the fruit you have just taken, and the effect also seems to be very variable.
Ketoconazole po is no longer approved in Europe.


Ketoconazol is still available here in the Netherlands but I would just get packaged grapefruit juice or if you are a physician just prescribe it yourself. I do and my insurance just reimburses me

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Oh thank you Arhu!
I didn’t know that. I looked in Switzerland (where I live) and in Germany, I have access there, but couldn’t find it listed in either of these countries.
I’ll see if I can order it in the Netherlands via an international pharmacy (if it’s not approved here, importing it shouldn’t be such a problem). With ketoconazole the booster effect seems to be quite consistent.
Prescribing it myself is absolutely no problem - reimbursement via insurance is more of a hindrance…
Does your insurance pay for rapamune?
Heretically speaking, we don’t necessarily have to care about the dose and the final blood level, as we don’t know what it should be or how much or little is good.
But there is at least an empirical view/ an educated guess of a dose of pure sirolimus (corresponding to 6-ca 12mg/week?) that seems at least reasonably safe for our purposes, so we would like to be in about that range, with or without booster


Yes but I feel somewhat bad about it so I have been taking it with grapefruit juice anyway.

4mg with grapefruit juice/week eventually turned out to be too much because after a few months I ended up with a painful erosive stomatitis

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It’s honorable that you feel uncomfortable imposing this on the community and therefore take GFJ
I hope your mouth ulcerations have healed quickly…
I currently take 1-2mg with GFJ weekly.
we shouldn’t overdo it as long as there is zero data on humans. Otherwise we’ll end up living shorter instead of longer.

Apparently the community perceives oral ulcers as harmless. But I’m not entirely sure about that either and there is no data or none that I know of. Of the patients I have seen with oral ulcers/stomatitis (chemotherapy, MTX overdose) and who have had a colonoscopy for various reasons, quite a few have also had ulcerations in the intestinal mucosa and I don’t know whether this is healthy. Unfortunately, ulcers in the intestine do not necessarily manifest themselves spontaneously.


Not certain what “6-ca” means.
Clarification please.
Did you intend to write 6 mg - 12 mg per week?

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Welcome, and I hope you have a positive experience with sirolimus.
Not all of us in this forum experience negative side effects from “normal?” dosing.
I am an 83-year-old male who has been taking rapamycin for over two years experimenting with various dosages. I have had zero side effects other than a day or two of mild diarrhea when I have overdosed, not a single pimple, mouth sore, or any other skin or digestive tract symptom. Currently, I take 4mg/weekly with grapefruit juice.


I would guess it means circa

Yes, I meant 6mg up to circa 12mg
Sorry if that was unclear

@desertshores: thank you for the welcome!It is great that you can take 4mg/d with GFJ without side effects. This makes it even more complicated that the tolerance varies greatly from person to person

But maybe I’m also too skeptical with all this…


Anecdotally. I don’t see older folks in the forum complaining about side effects as much as younger members.
I wish Dr. Greene would publish the incidence of side effects among his older patients as compared to his younger ones.


I’m taking Ritonavir + Sirolimus, so my wife and mother.

I’ve used some papers to estimate the correct intake of R+S.
There was a paper on R+S+X (3D dosing regime or so) there I got some info.
There was also a paper on Paxlovid. They are using 200mg of R in paxlovid to get rid of CYP3A4/5.
I think there was another Paper but I’m not sure ATM. There were many papers I read, also on furanocumarins (the reason Grapefruits inhibit Cyp3A4 - they only inhibit 3A4, not 3A5 - we can’t be sure which one is active and which is not. We can only do a statistical assumption)

And yes, it wasn’t possible to estimate the Cmax that way. It’s interessting to know, but I don’t see a real reason for measuring it.
I came to the conclussion that in the best case, CYP3A4/5 will need 3 days to rebuild completely so I would be on the safe side to take R(200mg)+S(2mg), every 10 days.
Because I am 44, I decided to take it only every other week. There is no need to rush things.

I think about changing the dosing regime for my mother to every 10 days. But before I’ll do that, I do one single blood test. I just want to know the blood levels 72h after taking Ritonavir. The rest is just doing some math.

I’m taking Sirolimus for 20 months or so. I’ve started with S+GF, but Grapefruits are nearly as expensive as a pill of Sirolimus here and of cause I don’t like the effect of the furanocumarins: I just got more sunburns while taking it.

I also noticed that some GFs having more furanocumarins then others. So I’ve tested an IPL laser at the inside of my forearm after eating a GF. In some cases I got mild burns at low levels, in some cases not.
I think the problem here is that or supermarkets store them for to long. The furanocumarins just get lost after a while.
Same problem should be if taking GFJ instead of whole GF.

Besides, I’m taking R+S for 16 months or so with no side effects.
my mother and wife are taking R+S since 8 and 4 months. Also no side effects.

I was also testing 6mg S + 200mg R for one time before giving it to my mother. Also no side effect.

Oh … and uhm… welcome to the forum. :slight_smile:

My posting about the furanocumarine paper and GFJ

here is why I came to the conclussion that eating a whole GF is better then drinkling GFJ
My goal before was to mix a standardised drink with all the ingredients necessary to inhibit CYP3A4.

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5mg per week for 6-10 weeks works wonders!

Dear forum members, thanks for the thoughts and for sharing your sirolumus dosing regimens with grapefruit juice and other substances
@ Qurestine: Thank you for your detailed comments and the reference to the other thread.
Regarding ritonavir, I find it remarkable that there are not so many sources, considering that it has been and is taken billions of times (as a booster of currently e.g. Paxlovid as you say, but also for about 30 years in HIV therapy in combination with protease inhibitors).
In this respect, I find it interesting because it is cheap and safe, but what puts me off is the irreversible inhibition of CYP3A4/5 and the estimated but completely unclear duration of action.
At least 3.5 days (enterocytes), but completely unclear in hepatocytes.

Int. J. Mol. Sci. 2022, 23(17), 9866; IJMS | Free Full-Text | The Mechanism-Based Inactivation of CYP3A4 by Ritonavir: What Mechanism?

Despite the reversible inhibitive nature of ketoconazole, the clinical CYP3A inactivation capacity of ritonavir appears only modestly higher in contrast with the inhibitory potency of itraconazole, which is significantly lower than that of ritonavir [48]. As a consequence of the irreversible action, once CYP3A is inhibited by ritonavir in vivo, it will remain nonfunctional, and only its replacement with newly synthesized CYP3A will lead to a recurrence of CYP3A activity. The duration of the inhibition should thus to a large extent be dependent on the CYP3A turnover rate in the tissues in question, which might be quite rapid, especially in the small intestine, where entire human enterocytes have a turnover period of only about 3.5 days [49]. Interestingly, there is no consensus in the literature about the clinical recovery time of CYP3A activity after the discontinuation of ritonavir. For example, a study by Culm-Merdek et al. (2006) described nearly full recovery after a three-day washout period, whereas Katzenmaier et al. (2011) observed the inactivity of the enzyme even after three days [50,51]. The former results would appear to be more in line with the known turnover rate of enterocytes, but the replacement of CYP3A in hepatocytes could be considerably slower.

In this respect, it could be that one is exposed to a very high AUC, here we do not know at all whether this is good or bad…the tendency of the “users” is more towards single high doses with breaks in between.
I researched this again today and found the above publication.
But it’s interesting to know that ritonavir/sirolimus is doable and apparently tolerated without any problems.
Blood level measurements seem feasible but cumbersome, expensive and complicated to interpret.
In this respect, grapefruit juice or possibly ketoconazole is the only options for me at the moment.

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There are also other options for increasing AUC/ half life of Rapamycin (but also hard to get or with some side effects):

  • Voriconazole
  • Erytromycinum
  • Orungal

Macrolides such as erythromycin might also be an option, that’s true.
Voriconazole is a highly potent antifungal medication that I occasionally have to prescribe to seriously ill patients. It is very expensive and has many side effects, so I don’t think it is a suitable biohacking medication.

I would be very hesitant to combine Paxlovid / Ritonavir with Rapa as Pfizer has just re-emphasized potential life-threatening side effects or even deadly complications in a warning of the German health agency : Sorry it’s in German

Btw I get my Rapa from Turkey where it is a fifth of the price in Germany.

Thank you.
However, this probably mainly affects people who take sirolimus daily, usually in combination with ciclosporin, as the combination with ritonavir/paxlovide very quickly leads to very high, potentially toxic through levels of both substances.
Unfortunately, there is no data (that I am aware of) for a single dose of sirolimus in combination with ritonavir every week.
In this respect, it is probably wiser overall to simply take sirolimus pure without ritonavir or other substances. But this can of course be very expensive in the long run.
May I ask you how you manage to import sirolimus from Turkey to Germany? Isn’t it confiscated by customs?

overdosing Sirlolimus is very difficult, esp in our case. There were some papers there they gave sirlolimus as an anti cancer treatment in insanly high dosages (50mg daily over months). No serious adverse events despite sickness and so one. However, they turned to a twice daily dosage of 25mg.

Overdosing Sirlolimus only works if you completely inactivate mTor (=deadly within minutes). This is only possible as Dr_Wintermute pointed out, if you take Sirolimus as an immunosuppressant while beeing on paxlovid or ritonavir for some days. :wink: