Improve Bioavailability of Rapamycin (2)

Anyone looked into Cobicistat?

Cobicistat: A case of mislabelled drug‐drug interaction risk?
DOI: 10.1111/bcp.14262

Cobicistat was licensed as a stand‐alone formulation by the European Medicines Agency (EMA) under the tradename Tybost® in 2013. Remarkably, cobicistat does not have a therapeutic effect on its own, but only acts as a CYP3A inhibitor. As a result, it improves oral bioavailability and reduces systemic clearance of CYP3A substrates. Cobicistat’s indication is to increase plasma concentrations of certain antiretroviral agents, such as atazanavir, elvitegravir, or darunavir; this is also called “pharmaco‐enhancement.” Cobicistat is mainly used as part of fixed‐dose combinations for the treatment of HIV infection, such as Stribild® or Genvoya® (boosted agent is elvitegravir) and Rezolsta® or Symtuza® (boosted agent is darunavir).

Cobicistat Versus Ritonavir: Similar Pharmacokinetic Enhancers But Some Important Differences
DOI: 10.1177/1060028017717018

Cobicistat is a structural analogue of ritonavir without antiviral activity. It has improved physiochemical properties compared to ritonavir and is a potent inhibitor of CYP3A and a weak inhibitor of CYP2D6. Cobicistat inhibits the transporters P-gp, BCRP, OATP1B1 and OATP1B3.8 Cobicistat 150 mg once daily has a pharmacokinetic boosting effect comparable with ritonavir 100 mg once daily.9

In contrast to ritonavir, cobicistat does not demonstrate any enzyme inducing effects on CYP450, UGT or P-gp.8 There is reduced activation of the pregnane X receptor which regulates expression of different drug-metabolizing enzymes and demonstrates the reduced impact of cobicistat on concomitant medications.10

[***]

Recently, an in vitro study demonstrated that ritonavir was more potent than cobicistat in overcoming rifampin-induced increase in darunavir clearance.45 These findings, along with the etravirine, tipranavir, carbamazepine and rifabutin interaction studies suggest that cobicistat may not be as effective as ritonavir in overcoming CYP3A4 induction in the presence of concomitant inducers. Therefore, coadministration of cobicistat-regimens with moderate-potent enzyme inducers should be avoided.

Ritonavir is the best alternative to ketoconazole as an index inhibitor of cytochrome P450-3A in drug–drug interaction studies
DOI: 10.1111/bcp.12668

Mean (± SE) RAUC values were: ketoconazole (15 studies, 131 subjects), 11.5 (±1.2); itraconazole (five studies, 48 subjects), 7.3 (±1.0); clarithromycin (five studies, 73 subjects), 6.5 (±10.9); and ritonavir (13 studies, 159 subjects), 14.5 (±2.0). Differences among inhibitors were significant (F = 5.31, P < 0.005). RAUC values were not significantly related to inhibitor dosage or to duration of inhibitor pre-exposure prior to administration of MDZ.

[…]

In a DDI study directly comparing the inhibitory effect of 200 mg cobicistat and 100 mg ritonavir on clearance of oral midazolam, the mean RAUC values for midazolam were 19.0 for cobicistat and 23.9 for ritonavir

Cobicistat versus ritonavir boosting and differences in the drug–drug interaction profiles with co-medications
DOI: 10.1093/jac/dkw032

Boosting axitinib exposure with a CYP3A4 inhibitor, making axitinib treatment personal
DOI: 10.1080/0284186X.2017.1311024

Inhibition of human cytochromes P450 in vitro by ritonavir and cobicistat
DOI: 10.1111/jphp.12820

Ritonavir and cobicistat both were strong inhibitors of CYP3A4, with IC50 values of 0.014 and 0.032 μm, respectively.

In-vitro inhibitory potency of ritonavir, cobicistat, and positive control inhibitors vs 6 human CYP isoforms
DOI: 10.1111/jphp.12820

Table 2

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There are many other ways to enhance bioavailability that are commonly used in pharma and “GRAS”.

Sodium caprate (one MCT in coconut oil) is one way. It’s about 2x for hydrophilic Berberine.

Example:

This is great info- I definitely over did it this time, with annoying mouth sores for over a week and fatigue. I always felt fine until last week with GF juice on a double down dosage (lesson learned), I tend to be an overachiever LOL!

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Agree! Some folks are testing at more than 3X,s higher with GF juice.

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I came to the same conclusion and just took my first dose of rapamycin last weekend fasted but i don’t know if it’s best with food. Do you take Rapa fasted? if not what kind of food do you eat with Rapa? Right now my thinking is to dose at 6mg / week.

While some take rapamycin when starting a Fast, i prefer it do it when i am in ketosis… And take it with a high fat meal. More info also on dosing here: What is the Rapamycin Dosing / Dosage for Anti-Aging or Longevity, and Life Extension?

Apparently you get better bioavailability of pills if you take them leaning to the right side, whether you are sitting, standing, or lying down. The longer you stay there, the faster your pill gets sent to you intestines.

from the linked article:

The team was very surprised to find that if a pill takes 10 minutes to dissolve on the right side, it could take 23 minutes to dissolve in an upright posture and over 100 minutes when laying on the left side

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I’d prefer to take it in an already fasted state (that just seems logical to me); but, obviously, the bioavailability makes that a no. I’ve considered getting ketoconazole pills to increase bioavailability in a fasted state. I just need to do some research to determine any tangible downside to once/week ketoconazole.

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This one has me scratching my head. We really don’t want the coating of the Rapa pills to dissolve do we? Doesn’t stomach acid wreck the active ingredient? Also we know that a fatty meal improves absorption, and a fatty meal slows down digestion.

Great article and probably works well for supplements to lay on your right side, but for Rapa doesn’t this mean you should lay on your left?

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Interesting, but may not be relevant to the one-day per week, or every other week dosing with rapamycin.

They were only seeing increased AML after 14 days use.

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Thanks for all this. From this information I will experiment a bit with grapefruit and fat when taking Rapamicyn.

Unfortunately, I do not see (at least on this thread) comments about the bioavailability of the most common tablets people is using. What is the bioavailability of Indian generics Rapacan, Siromus and other generics tablets? Is one better than others? (This is my main question: which generic to buy when considering bioavailability?) Or are these generics considered to have decent bioavailability? What about when compared to Pfizer product?

Also, is grapefruit + fat + generic tablets enough? Or do we really need to find a way of coating the tablets? Kaeberlein mentioned in his most recent podcast with Attia that coating of Rapamicyn was of high importance for bioavalilability. And this lead to the discovery of his “favorite” mice experiment that late in life treatment is possible, leading to Gerontorogical use of the drug.

I have been using 0.15mg of Rapacan per kg of weight once a week for a while. No side effects but really no effects at all (that I can feel). But I was not aware of the bioavailability issue until I heard the Attia podcast with Kaeberlein last week. Any ideas on how to “feel-it”? (I can’t measure blood levels here without GP prescription.) I was expecting my toe nail fungus to disappear, but it is still there. Now I’m suspicious of low bioavaliability.

Many many thanks for this.
Dr. Spin

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Hi All, I may be unique with my rapa absorption problem, I can’t swallow pills. All pills need to be blended into a slurry in a bullet grinder. I blood test via the lifeextension.com via labcorp sirolimus blood test ($99). You have to call their support number then ask for blood testing, support and eventually they will find who can sell this test. Its not on their website.

First of all; any have a good guess at what blood concentration I should be shooting for? 20ng/ml? 40ng/ml? The blood test states a range of 3-20ng/ml. I’ve seen absorbtion studies in this threa mentioning 40 and up to 70ng/ml…

My highest test results so far is 7.2 ng/ml and this was after this dosing protocol;

  • each day, 2 days every 2 weeks; In the morning; (attempts to increase aborbtion) 1T dried GF powder, 1T GF extract, peperine 10mg, 2T olive oil. I’ve already been filled in re the value of frozen GF concentrate vs my attempts to be simplier with dried GF powders.

Then 2 hrs later, giving time for CYP34A to be suppressed.

2t olive oil + 10mg via 1mg indian sourced sirolimus pills, tossed in 6mg via diluted down pure chinese powder (just for good measure). IE kitchen sink approach.

One the 3rd day I had blood draw for the sirolimus blood test and got 7.2.

== Improvements I’ll add gleened from above (thanks all)

  • During the pre-dose dose I’ll add additional CYP3A4 suppressors:

  • 1/2 can of frozen GF concentrate. Yes giving in and just have this product flowing through the freezer.

  • 1g berberine

  • 1g fiesitin

  • 1g sodiumm caprate (an MCT/coconut oill derivative)

Then reblood test.

=== General comment to other DIY rapa experimentors.

Given my close inspection of my indian 1mg pills, I found them to be fragile, easily broken and crushed. I wonder if they are at all enteric? Disolve in the stomach much likee my grinding and drinking a slurry?

You guys may not be achieving the blood levels that are beneficial?? Given the risk to true benefit and variability of the sirolimus / rapa drug pill / supply chain. Do you really know what blood levels you are achieving?

Just a comment; I would suggest that everyone doing this protocol should do at least a few blood tests to verify for their (your) stomach, pills, protocol you are really getting the benefit you want.

I agree that canker sores and other symptoms are useful.

Rambling a bit; My opinion re canker sores to me says; your immune system is marginal to begin with and the initial function of rapa to (in theory temporarily knock down your immune system) causes the always present canker sore (like shingles like many lurking bugs). My question is why is your immune system marginal in the first place? Just questioning.

Not sure if my having no symptoms post rapa means much good or bad. Just plodding along, collecting data.

Not detailed; I do a 2day dosing of the classic D+Q+F (and kitchen sink add ons) scenolitic protocol on the alternating weeks.

Best to all, curt

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You test on day 3? Max is 2 hours after you swallow the pills. It goes down pretty quick.

That could be why you get low numbers.

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What do you think about putting the Sirolimus pills inside these? https://amzn.to/3qJ8deK

The generic Sirolimus I get from Amazon pharmacy are tiny and I’m now worried about stomach acid.

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It seems like the thing to do, but I would say if you don’t test, you won’t know.

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Has anyone done a test with the generic Zydus pills to see if there are any problems?

Apparently this Rapamycin he’s referring to was Zydus:

Also for what it’s worth ive been taking 6mg of Zydus for the past few weeks (I just started Rapamycin) and have had a mouth ulcer and high postprandial glucose after my Rapa dose for 24-48 hrs (with higher carb foods). These seem to be common side effects of Rapamycin, so that’s something.

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Yes, I got 3 canker sores after I took my 2 mg dose of Zydus + GFJ yesterday. Makes me wonder about my immune system. Although I have been exposed to COVID frequently and have never gotten it. So I am not sure how good my immune system is.

Although there is no euphoric or nauseous feeling like I had last week. That was probably due to dehydration due to cycling in very hot weather.

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It has been suggested that such capsules are not truly enteric coated. It appears the capsules are not ‘airtight’ where the two halves meet and liquid will still be able to get in and out of the capsule. (I believe it was Mac who suggested this, and he may very well be right about that).

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