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…
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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.
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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. 
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 https://www.bfarm.de/SharedDocs/Risikoinformationen/Pharmakovigilanz/DE/RHB/2024/rhb-paxlovid.pdf?__blob=publicationFile
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. 
I’d still go for Grapefruit juice to boost my dose 
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I get it when traveling personally or friends/patients go over to turkey. Can’t have it sent, it won’t go through customs.
Yes, there are some things still unclear and yes, my wife also gave me the name “labratory mouse” for that and she’s absolutely right.
Because of the unknown stuff I just decided to give me some extra days for washout in my dosing regime.
There are some reasons that kept me off ritonavir for a while:
a) lowered uptake of orally administered vitamines such as B12 and D3 and so on
b) I have a relatively strict diet plan for longevity propose that is far away from the DGE (like FDA)-believes for what is good for me and I am acutally sure that it will interact in some ways with CYP3A
c) I already eat lots of foods which inhibit CYP3A4 (i.E. Goji Berries)
on the other hand I have a relatively white skin so I am actually sensitive to the sun. I tried furanocoumarines first as I wrote but it wasn’t an option for the long term.
But I have no concerns on a high AUC. Seems at least for me that a high AUC is beneficial. So i decided to take ritonavir with a safety washout period.
I’ve also checked some blood markers (some=6 pages) and they are all going into the right direction. So I think I am on the safe side. But I think of doing the next blood count without my medical just to test all the markers I really want to have, including sirolimus. Is there something I need to know if I would send my blood to a lab?
If it is possible for me as a non m.d., I can answer your first question a little bit better.
I also ordered twice from turkey over a ‘trader’ who sends from within the EU (link is somethere here in the forum, search the ordering from turkey thread). Its ~3,50€ per Pill.
I also tried importing S as pure substance or as pills as a company. No way.
If I was from austria or switzerland, I just would travel to slovenia to buy me large amounts of S in the local pharmacys. I think it’s ~2€ per Pill. S is relativley cheap in east & south-east european countries, such as slovenia, slovakia and so on.
Cheapest legal source close by for me is a pharmacy in the netherlands. 4€ per pill. 4,50€ if ordered online (to germany).
Regarding the number of papers on ritonavir, found that remarkable too… seems like the pharma industry dosn’t care about if a drug is widely used or not, but the price seems to matter. On the other hand it seems that the first class of HIV pharmaceuticals aren’t an option anymore for HIV-patients.
Thanks for the comments & info about Turkey and Slovenia. In terms of cost, it just seems difficult to get it cheaply in Europe. So if I ever come to Slovenia, I’ll have a look at the pharmacy there, preferably in combination with a vacation
Sirolimus seems to be less toxic acutely, but I would still have great respect for a chronic overdose. It may be that a certain blockade prolongs autophagy and thus perhaps health or lifespan. However, mTORC1 has vital functions (nerve cells, insulin metabolism, glucose metabolism, muscles, immune system), otherwise it would not have been conserved across several species.
In this respect, excessive inhibition does not seem desirable. I have also seen patients with substantial immunosuppression and bacterial infections under relatively low daily doses of mTor inhibitors.
With regard to blood tests, a lipid panel, HOMA index and a small blood count might be useful with sirolimus.
Level measurements (Sirolimus) are common, but only validated for daily dosing. In this case, a trough level would be taken after a few days to ensure that it is within the defined target range for immunosuppression. At most, you could take a trough level a few days after taking it to see that it is not in the toxic range, but it shouldn’t be if you take it responsibly. AUC is very cumbersome and expensive to measure (several blood draws necessary)
Perhaps colleagues who frequently prescribe this for our purposes have other suggestions, but in general it is often the case in medicine that more measurements don`t necessarily bring more benefits
I’ve checked lipids twice and full blood count once near my rapa intake.
In short: its fantastic. Blood glucose is at normal level, hba1c is fine but because of my diet it should have been lower.
it is maybe due to the sirolimus intake.
If the exact levels are interessting for you, I’ll add them in here but I don’t think that it is neccesary to check them again.
The last checkup was due to some issues at the nephrology. I asked them to check sirolimus blood levels but they refused to check off label taken drugs. Next time I’ll try it again with a referral. I don’t know yet how often they will check sirolimus blood levels, I only know they will.
my idea is to check them at day 4 after intake (exactly 96h after intake). It should be possible to extrapolate the curve from that point on. Don’t you think?
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That’s good news about your blood values! Are you following a special diet if you suspect your HbA1C should be lower? Did you have this and the lipids checked before taking sirolimus?
I’m still skeptical about sirolimus levels: maybe it makes sense to check that you’re not in a rather toxic range, but we don’t have any reference values for non-daily doses. There are only reference values for organ transplant patients, but at around 4-12 (20) ng/dL (through, i.e. directly before the next administration) they have a significant immunosuppression. You should certainly not be above that. However, this raises the question of when to measure when taking weekly or biweekly doses? The half-life is long (several days) so it could be that 96 hours after taking it is a good time…The way I see it, one cannot extrapolate AUC from just one value.
As I understand it, you can’t extrapolate AUC from just one value. But I’m not a pharmacologist… But even if we could determine the AUC we wouldn’t know what value we want to reach…
lipids:
I dont have enough data to be absolutley sure about this. My lipids tend to be more or less stable (=within a really health range)
My diet is a more or less vegan whole food diet. I included fish (esp. sardines) as well after some months on a completely vegan diet because my blood markers didn’t show any improvments (lesser triglycerides, okay, but that’s only the whole count for triglycerides, specific trigylcerides wern’t listed)
Diet:
200-300g dark green leafs (with lesser oxalate content)
30-100g nuts and seeds (mostly walnuts, almonds and sunflower seeds, linseeds)
min 500g vegetables in general (without dark green leafs)
fibre: mostly between 50-70g/day, seldon more
oils: mostly olive, linseed and rapeseed also included
25-50g wheat germ/day (because of the vitamine profile and spermidine)
but I did also eat a lot of fruits and berries:
blueberrys 100g/d (european wild berries)
other berries: 100g/d
20g other vacciniae berries
300g of other fruits such as apples, oranges, cataloupes, plums, mangos
I try to reduce it until I see the data for my next blood test. For example: mangos are high in sugar (not fructose)
If I eat grains, it is always whole grain but not wheat (to much sugar).
If I eat bread, it is selfmade from sourdough
main goals per day:
500mg of carotinoides,
50g digestible fibre,
high polyphenole content,
and as much as folate and selenium as I can get from a healthy diet.
None vitamine/mineral should be lesser then 150% RDA.
Also a goal: using diet instead of acarbose - and yes, at least in my case is seems to be possible
It took me a while to figure out which diet is best for me. I started with the diet used from fitzgerald et al. but modified it a lot and also included data from michael lustgarden.
What I can say is: my blood sugre levels (non of them) don’t run rampant on rapa days.
concerning AUC:
yes, you’re right. It is more a good basis for a qualified guessing based on average data. I should also measure Cmax.