Rapamycin Method of Delivery, Considerations

[RapAdmin]

@MAC

Subcutaneous nanotherapy repurposes the immunosuppressive mechanism of rapamycin to enhance allogeneic islet graft viability

(link to paper here)

Thanks for posting this paper as I had not come across it before. I find this statement interesting:

With regards to biodistribution, lipophilic Rapamune primarily partitions into red blood cells (95%) and then eventually accumulates in off-target organs, including the heart, kidneys, intestines, and testes,

While the paper above is focused on the issue of “off-target” effects when delivered as part of a therapy for transplanted cells and tissue, we in the longevity community want (I suspect) rapamycin distributed to as many tissues and cells of the body, so the issue isn’t so much of “off-target” problems, but rather lack of the drug getting to some organs or cells enough so as to slow aging.

It seems that one of the issues we want to think about is that with oral (tablet-based) rapamycin there is a natural distribution pattern / effect throughout the body and I don’t know exactly what that distribution or effect pattern is. It would be interesting (for me at least) to better understand exactly where rapamycin is typically dispersed, and how well it gets into all the different tissue types, and organs. Perhaps different rapalogs have different distribution patterns?

@MAC I know you are much less injection-adverse than I am - but it seems it would be interesting to understand and compare the distribution pattern of injectable rapamycin (rapalogs) like Temsirolimus. I wonder if they might be complimentary in terms of their benefits WRT organ and tissue distribution due to the different administration method and how it acts (more as a prodrug than simple mTOR inhibitor.

Temsirolimus also has a very short half life of 17 hours or so - about 70% shorter than rapamycin, so likely a much better side effect profile and lower risk of immune suppression.

Its a little hard to parse the Google Patent database to find out when Wyeth first patented Temsirolimus (Torisel) but it seems likely to have been in the late 1990s or early 2000s - in which case its soon going off-patent, if it hasn’t already. Not sure if the market is sufficiently large to justify a generic form… but researchers should be evaluating it for lifespan improvements. And of course, it would be great to know the lifespan effects of injection methods, vs. oral tablet rapamycin use, and different combinations of the rapalogs and administration approaches. So many avenues still to discover with this drug… and how to optimize its longevity effect.

Temsirolimus

My google patent search:

Google Patents

This patent did look interesting though:

Rapamycin analogues and the uses thereof in the treatment of neurological disorders

US7470682B2 - Rapamycin analogues and the uses thereof in the treatment of...

[RapAdmin]

@MAC replied:

@RapAdmin

it seems it would be interesting to understand and compare the distribution pattern of injectable rapamycin

This is a completely separate and complex rabbit hole. The method of delivery completely changes the pharmacology/pharmacokinetics.

Drugabs.pdf

There is HUGE advantage to bypassing oral with other parenteral routes…you eliminate 1st pass metabolism, a chronic problem with oral delivery, ie, rapamycin (eg. the seminal rapamycin/intranasal study). Not only can you massively increase bioavailability, you can theoretically also BYPASS many of the side effects associated with liver (lipids, glucose, liver enzymes, etc…)

Once you decide to bypass oral, then that dives into yet another layer of delivery mechanics, biovailability, systemic targets, formulation, dosing, distribution, etc.

An example of oral vs intramuscular on JUST kinetics, same drug.

Schematic of oral vs intramuscular, again, bypassing the liver:

Sublingual vs Oral:

Oral vs IM:

Intramuscular Injection

IM Advantages
• Rapid and uniform absorption of the drug, especially the aqueous solutions
• Rapid onset of the action compared to that of the oral and the subcutaneous routes
• IM injection bypasses the first-pass metabolism of the drug
• It also avoids the gastric factors governing drug absorption
• Has efficacy and potency comparable to that of the intravenous drug delivery system
• Highly effective for emergency scenarios such as acute psychosis and status epilepticus
• Depot injections allow slow, sustained, and prolonged drug action
• A large volume of the drug can be administered compared to the subcutaneous route

Disadvantages
• The absorption of the drug is determined by the bulk of the muscle and its vascularity
• The onset and duration of the action of the drug are not adjustable
• Inadvertent injection within the subcutaneous plane can lead to delayed action of the drug
• Suspensions, as well as oily drugs, cannot be administered

An intramuscular injection study of Siromilus in dogs:

Rapamycin Pharmacokinetic and Pharmacodynamic Relationships in Osteosarcoma: A Comparative Oncology Study in Dogs (IM)

pone.0011013.pdf

After choosing a non-oral method of delivery, the question then becomes distribution into the various compartments of the body…what tissues, organs, brain, etc. And this becomes a matter of the drug’s intrinsic chemical properties (eg. lipophilicity)

Drug Distribution - Drugs - MSD Manual Consumer Version

“Once absorbed, most drugs do not spread evenly throughout the body. Drugs that dissolve in water (water-soluble drugs), such as the antihypertensive drug atenolol, tend to stay within the blood and the fluid that surrounds cells (interstitial space). Drugs that dissolve in fat (fat-soluble drugs), such as the antianxiety drug clorazepate, tend to concentrate in fatty tissues. Other drugs concentrate mainly in only one small part of the body (for example, iodine concentrates mainly in the thyroid gland) because the tissues there have a special attraction for (affinity) and ability to retain that drug.”

Tacromilus oral vs IV:

Intravenous tacrolimus is a superior induction therapy for acute severe ulcerative colitis compared to oral tacrolimus

Intravenous tacrolimus is a superior induction therapy for acute severe...

"Intravenous TAC is a way to circumvent the low bioavailability of oral TAC and allows the target concentration to be reached rapidly, continuously, and stably. This superior aspect very much contributed to its safety profile; we found no differences in adverse events between oral and intravenous TAC."

Tacromilus IM vs Oral in monkeys:

Reduced variability in tacrolimus pharmacokinetics following intramuscular injection compared to oral administration in cynomolgus monkeys: Investigating optimal dosing regimens
https://sci-hub.se/10.1016/j.jphs.2018.05.013

“The dose of tacrolimus were 0.1 mg/kg (3-4 kg monkeys = 0.4mg) for IM injections and 5 mg/head for oral administrations (difference 12.5X dosing). The mean oral bioavailability of tacrolimus relative to the IM injection was estimated be 4.8% while mean relative bioavailability of IM injection was assumed to be 100%. In the case of tacrolimus, we have shown that IM injections reduce the variability for parameters that have importance in the therapeutic exposure of the drug. Furthermore, this study indicates that long-acting IM injections could prove useful for tacrolimus. The advantages of reduced variability combined with sustained release shown in this study for the IM injection of tacrolimus could warrant a new strategy for administering tacrolimus.”

I am going to stop here (server overload, LOL) because I don’t know enough yet about the IM biodistribution of rapamycin or other rapalogs to give more meaningful insight to the real thrust of your question. WIP, stay tuned…

[RapAdmin]

@MAC further replied:

Rapalogs and mTOR inhibitors as anti-aging therapeutics (LAMMING, 2013)

https://www.researchgate.net/publication/235775808_Rapalogs_and_mTOR_inhibitors_as_anti-aging_therapeutics

[EnrQay]

I’d be very interested on the effect of sublingual rapamycin. For instance, would overall absorption be higher or would it be absorbed at all sublingually? Would the peak plasma concentration be greater? Would it, through a possibly higher peak and through the sublingual conduit, penetrate the blood-brain barrier more readily?

[MAC]

Briefly, most definitely an alternative route, bypasses 1st pass gastric, offers rapid absorption, higher Cmax, and higher bioavailability. There is ample nervation in the oral cavity and reduced enzymatic degradation (vs gastric). It can alter the systemic biodistribution and compartment allocation (organs, fat, muscle, brain, lymphatic, etc). Both IN and SL, with the facial nervation, can offer faster and potentially greater access to the CNS/BBB. It would need to be properly formulated (see Everolimus example below) for optimal delivery.

Sublingual administration

https://jpharmsci.org/action/showPdf?pii=S0022-3549(16)30352-5

“The following sequence of events flow to systemically deliver drug via the buccal/SL route: first, drug presented to the oral cavity must be released from the formulation (tablet, patch, lozenge, film, or gel dosage form); second, the drug must rapidly dissolve in saliva; third, the drug must partition into the epithelial lining; forth, the drug must diffuse across the epithelial barrier; and lastly be cleared into the systemic circulation. Absorbed drug is drained into the internal jugular vein, bypassing gut and hepatic first-pass metabolism”

In fact, it’s already being used clinically with some rapalogs (to help bypass typical oral issues, patients unable to take orally)

Sublingual Tacrolimus: A Pharmacokinetic Evaluation Pilot Study
https://sci-hub.se/https://doi.org/10.1002/phar.1149

“Sublingual administration of tacrolimus was accomplished by opening commercially available tacrolimus capsules and placing the powdered contents under the patient’s tongue. To allow time for drug absorption, patients were told to avoid swallowing for 5 minutes and to not eat or drink for 15 minutes.”

Sublingual tacrolimus as an alternative to oral administration for solid organ transplant recipients
https://sci-hub.se/10.2146/ajhp140322

Designing orodispersible films containing everolimus for enhanced compliance and bioavailability
https://sci-hub.se/10.1080/17425247.2020.1828342

“The use of an orally dissolving, permeable film delivery system can serve
as a more efficient alternative to deliver everolimus” (this is an example of how the drug is formulated for SL clinical use)

Oral Dosage Forms That Should Not Be Crushed

Everolimus and Rapamycin listed (this is just default pharma efficacy disclosure)

Just for fun, I threw some rapamycin powder under my tongue…it was not visible after 10 mins. I was very careful not to move my tongue, or swallow and maintain position and saliva pool…just to let it percolate.

[MAC]

Some information on rapamycin tissue distribution in rats, IV vs oral rapamycin.

Distribution of sirolimus in rat tissue (1997)
https://sci-hub.se/10.1016/s0009-9120(96)00157-9

Takeaways from chart below (A = IV, B = ORAL) They didn’t measure brain! Argh.

1. Oral bioavailability is 5% of IV. Same in rabbits, and similar in humans. A massive negative for oral, along with huge inter person variation.

2. Rapamycin (and its metabolites) is widely distributed across tissues, high volume of distribution, both oral and IV, although MUCH higher rapamycin tissue levels in IV vs oral, at lower dose.

3. For ORAL, much higher level of rapamycin in the INTESTINE vs IV, even though lower doses and bioavailability. Indicates more rapamycin is trapped in the intestinal tract.

4. This is just major organs (sans brain), not fat, muscle, lymphatic and other compartments.

5. The ROUTE OF DELIVERY profoundly impacts dosing, bioavailability, target tissue concentration, and quite possibly, therapeutic efficacy (both target organ (1) and systemic) and side effects. This is widely known with other drugs, rapamycin is no different, except not fully explored…that human impediment thing, biology does not care.

(1) The subcutaneous/nano rapamycin paper above, it was specifically designed to bypass systemic blood delivery to deliver efficacy. From an email exchange with one of the authors: “standard sirolimus administration is intended as an immunosuppressant to inhibit T cells directly. Our strategy was to avoid this and instead modify dendritic cells and macrophages in the lymph node and spleen.”

Below graphs are NOT Rapamycin…Fentanyl, but just to show various tissue concentration.

[EnrQay]

In the sublingual experiment with the six patients,

The average maximum concentration was higher during sublingual administration than during oral administration

and the AUC was also higher for sublingual. Their conclusion:

dose conversion should be evaluated on an individual basis…a 2:1 oral-to-sublingual conversion may be appropriate when there are no concomitantly interacting drugs

I conclude this is a reasonable way to vary one’s intake of rapamycin, using a half-dose. I wouldn’t do this every time, but occasionally as a way to vary the concentration in different tissues…hopefully the brain would get a higher concentration.

[MAC]

@EnrQay

I conclude this is a reasonable way to vary one’s intake of rapamycin, using a half-dose. I wouldn’t do this every time, but occasionally as a way to vary the concentration in different tissues…hopefully the brain would get a higher concentration.

Certainly worth exploring in a controlled experiment type way, so you can try and separate signal.

[CTStan]

If one were to mix or vary the delivery method of rapamycin, is there any data to predict which organs or tissues would be affected differently and in which direction?

[MAC]

Your questions are a a bit above my pay grade…but now we’re engaging into exploring other modalities vs hitting our heads against a wall. We need to scale the castle wall…not be held back by the moat.

See the rat study and subcutaneous above as examples. Intranasal might give more of chance to penetrate more drug into the brain, as would say buccal, but lesser extent. Subcutaneous for more lymphatic. Intramuscular is almost like IV, but slower kinetics but requires special formulation.

For example, giving a dog IN could be huge…with their olfactory size and nervation vs human, could be great way to deliver and bypass oral. But would need special engineering considerations for dose/excepient/delivery method, same for say IM for dogs, albeit more systemic than brain.

With a drug like rapamycin, high inter-person variation, highly susceptible to gastric, intestinal, and liver destruction…oral SUCKS.

Like I said, still a WIP exploration, sharing some interim findings.

[CTStan]

@MAC

Intranasal might give more of chance to penetrate more drug into the brain, as would say buccal, but lesser extent.

Intriguing possibilities, not just for rapa but senolytics. Someone at the higher pay grade might be able to find relevant comparative studies and venture some educated guesses. The chance to “penetrate more drug into the brain” would definitely generate some interest.

[MAC]

ALL drugs are amenable to different routes of delivery.

Rapamcyin tissue distribution does not exist.

Educated guesses, certainly you can search the literature and get some insights.

Beyond that…you’re flying solo re exploring.

[MAC]

More in depth on sublingual:

Considerations in Developing Sublingual Tablets—An Overview

[EnrQay]

This article is pretty technical about its subject, but for me it boils down to: will rapa powder be absorbed? The paper about the six tacrolimus patients clearly showed it was. And for all the ways you can construct a tablet for superior sublingual absorption, isn’t putting powder under your tongue and not swallowing for 5 minutes and not eating or drinking for 15 minutes almost as good? You’ll get saliva carrying some down your throat, but I’d guess not much.

If excess saliva is a problem, perhaps dividing your dose into 2 or 3 parts, taken sequentially within a short time, would solve that.

[tongMD]

If excess saliva is the main problem, might I suggest waiting for any drugs already prescribed by your doc that cause dry mouth to take effect? There are quite a few, particularly stimulants that people take for various reasons and a lot of different possible “anti-aging” drugs… i.e. I’ve had to drink water/green tea constantly for ~10 hrs from Focalin XR with a relatively dry mouth because if I don’t, I’ll forget and I don’t want an increased risk of oral health issues.

Just as a reminder - one can measure serum rapa to see if sublingual works better.

[tongMD]

My concerns with IN is any nasal cavity conditions can make it harder to use or absorb ie mucosal inflammation/deviated septum/upper respiratory infection - not to mention possibly harmful long-term effects…I might use it for my DIY peptide nasal shots if there’s another pandemic but that’s it. It can be pretty hard to use.

[MAC]

@EnrQay

This article is pretty technical about its subject, but for me it boils down to: will rapa powder be absorbed?

100% some will be absorbed (sorry, article was more a pharma consideration). It might be net benefit though, trading off much lower absorption rate for less 1st pass metabolism loss. Rapamycin is more hydrophobic than tacromomilus. Theoretically, if you can get more into systemic without side effects, you should be getting more to cross the BBB (craniotomy/rapa/cancer study)

Good luck measuring brain levels.

The goal with any combination delivery modes would be to increase systemic delivery but LOWERED side effects.

If you really want to pursue, suggest dropping oral completely, doing a washout, and then doing ONLY sublingual re dose/trough/AUC vs oral.

[MAC]

@tongMD

My concerns with IN is any nasal cavity conditions can make it harder to use or absorb ie mucosal inflammation/deviated septum/upper respiratory infection - not to mention possibly harmful long-term effects. It can be pretty hard to use.

You are theoretically and clinically correct, but anything worth doing is hard…

We need to get around the “hard” impediment.

[tongMD]

I happen to know a RadOnc resident physician (they’re mostly doing research time anyways with a relatively cush 8-6) who may get C-11 sirolimus ordered or synthesized if one is getting a PET scan for some case study research that can quickly get approved and published at a >3 impact factor journal, but I need to formulate a decent ask and convincing pitch first…or one could go to India to get a PET scan for $100-200

Part of the reason I mention the former is that ultralow-dose PET (rarely used if ever - I’m not sure you can even get it done as a medical tourist in India) is possible in academia to reduce radiotracer dose and exposure - and can be done for full-body PET too. If one wants to know and doesn’t mind 100x less gamma radiation than a regular PET…that would probably be a far better option than a craniotomy.

[tongMD]

That’s technically true, but I find it can be more challenging to adhere to for the average person and ends up being less impactful to move the field forward unless there’s a significant benefit people are missing - that’s partly why NIH/NIA ITP was po.