Thanks, yes that was a typo on my 48.1 hours. Seems like there may be a lot of individual variation in half life. But this information you have given provides a rough guide on dosing levels people might try. It would be good if there is a low cost blood test to check trametinib blood levels over time.
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@cl-user I think you have some experience in this area⌠How would you interpret these results from low dosing where a lower dose results in a higher blood level? Is this just individual variability, or is there some other explanation you can think of?
There is individual variability especially for the peak height because that height is mostly the difference between the GI to blood absorption and the blood to organ distribution.
From a clinical point of view itâs mostly irrelevant for the organs though it might be for the blood cells.
Also that trial is totally underpowered. They have N=2 for 0.125mg and N=1 for 0.25mg.
Itâs the same with rapa. If you take it with a fatty meal the absorption is slowed down so the peak is lower but in the end you get more rapa into the organs.
Basically that peak is an artifact from the point of view of the organs. If your target is the blood itself then it can be relevant. Potential side effects (if they exist) on the blood cells of too high a peak in the blood could be significant though.
I think people wanting to experiment with that should measure their levels. At least the trough. (Same for rapa BTW)
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Ok, Iâve continued researching trametinib (Brand name Mekinist) and I think I may have identified some additional challenges that people may face if they are interested in trying this medicine for longevity purposes.
1. It doesnât seem that the tablets can be split / divided.
The tablets are film coated, and everywhere Iâve looked it seems that it is not recommended to split or divide or crush the trametinib tablets. While every drug company says this for most of their drugs so as to force you to buy the exact dose you need and pay more, in some cases its actually true for functional reasons. So far in my searching Iâve not been able to find anyone suggesting its ok to pill-split the trametinib tablets. This suggests that the lowest dose we can do is the 0.5mg tablet, (there is also a pediatric liquid formulation that can obviously be used in a more graduated dose, but liquid formulations are probably a little more difficult to get, store, etc.).
So - @cl-user , could you please run another pharmacokinetics graph with a dose of 0.5mg dose and see if you can identify what the frequency of dosing would be given the assumed half-life of 161 hours, and given an objective of trying to target an average blood concentration of between 0.1 and 0.2 ng/ml during the period between dosing?
This seems like the easiest dosing protocol (0.5mg once every X days) that people are likely to try to implement given the current tablet offerings.
Here are the references Iâve seen that have driven me towards this conclusion:
Sources:
2. Trametinib has refrigeration requirements (should be stored between 36 and 46 degrees F, or 2 and 8 degrees C).
Unfortunately, this makes it much more difficult to order this medication from India as there are no simple or inexpensive cold-shipment options available for medicines from India. The only viable option would seem to pick it up on a trip to India, and bring the medication back in a small, portable refrigeration option like that provided by the company called 4AllFamily.com: Voyager - Portable USB Travel Refrigerator for Insulin & Medicines â 4AllFamily
Source: Mekinist: Uses, dosage, side effects, cost, and more
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Neo
#81
@RapAdmin @cl-user These papers may have helpful references and they are much more recent that the 2013 trials. You might also find it valuable to talk with the authors:
Monitoring of Dabrafenib and Trametinib in Serum and Self-Sampled Capillary Blood in Patients with BRAFV600-Mutant Melanoma
Phase I pharmacokinetic study of single agent trametinib in patients with advanced cancer and hepatic dysfunction
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Neo
#82
Perhaps this could be a great product for Healthspan to do some mini trials on now and be ready to launch at the end of 2025 or so (@szalzala )?
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The problem is that 0.5mg goes to around 1ng/ml which is way above the 0.2 high target:
The only solutions to split the pill in 4 to get 0.125mg and use enteric coated capsules.
Even that has a delta of +0.18ng/ml so you canât stay above 0.1 without going to >0.2.
It needs to be split in 8 to be OK.
That said the individual variability is going to be a very important factor so this is just a proof of concept.
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Thank you! Good points, and good suggestions.
One additional issue: trametinib blood level testing
One other challenge Iâve run into is that there seem to be no commercially available trematinib blood level tests available from either Quest or Labcorp (or their resellers); Iâve searched on the websites. So, weâll likely have to lobby the lab testing groups to offer this. Given the wide interpersonal variations in blood levels weâve seen from the clinical trial testing, I think blood testing is likely going to be important, especially in the early days of adoption of this drug, if and when it happens.
Blood testing also important if people try to split the tablets and put the remaining portions into small enteric coated capsules; youâd want to make sure your encapsulation efforts are working as planned.
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@cl-user , is there a way that the software youâre using for the graphing also be used to calculate the total AUC over a given period of time (e.g. 60 days) given different dosing levels (mg), period of dosing (e.g. once every 6 days, or once every 20 days, or ever day), as well as the half-life estimate?
It seems that ideally we would want to not only compare the target blood concentration given any dosing protocol, but also understand how the total AUC over a given period compares in the longevity papers, our own testing/modelys, and the total AUC of the typical 2mg/day dosing of trametinib that is used in cancer treatment for which the side effect profile is well-defined.
For example, Iâd like to compare the total monthly AUC of the cancer dosing protocol (2mg/day) to the different pharmacokinetic models/graphs that youâve created; 0.5 mg every 22 days, 0.125mg every 20 days, 0.0625mg every 6 days, etc.
That would seem to give us the most accurate exposure level of the human body to the drug, and thus convey to some degree the risk of the âlongevity-dosingâ side effect profile compared to the side effect profile typical in cancer therapy routines.
Iâve been looking online for an online AUC calculator for ongoing dosing protocols, but havenât really been able to find any. Only these resources, which are a bit of a start on this issue:
Though perhaps Iâm digging too deep into the weeds on this.
We know from simple calculations that the two-month total dosing levels based on simple size of dose/frequency of dose would work out as follows, and perhaps this tells us enough. If weâre dosing at 1/50th to 1/100th the cancer treatment dosing levels, is there really much danger to people? (perhaps some pharmacologists can comment)âŚ
| Tramedinib Dose (mg) |
Frequency (every X days) |
Total 60 day dose |
Percent of Cancer Dosing Level |
| 2 |
1 |
60.00 |
100% |
| 0.5 |
22 |
1.36 |
2.27% |
| 0.250 |
16 |
0.94 |
1.56% |
| 0.125 |
20 |
0.38 |
0.63% |
| 0.125 |
13 |
0.58 |
0.96% |
| 0.0625 |
6 |
0.63 |
1.04% |
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Iâm using code I wrote in Julia in a Pluto interactive notebook.
No problem to compute the steady state average AUC/day. Itâs better than trying to eyeball it by looking at the curves. The half-life estimate is already in the plot legend but in this case Iâve set it to 161h as you requested because the data is not good enough to be able to get a better estimate and there are large individual variations anyway.
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FEDEX India does offer 2-3 day (guaranteed) shipment from India to USA (including customs clearance), and offer temperature controlled packing for 2 C to 8 C guaranteed over 96 hours. Probably costs more than the standard EMS by Indian Postal Service + USPS. There are IndiaMART sellers of Mounjaro Pens that claim 3 day delivery to USA.
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The issue is that typically you need a prescription (from US doctor, I think) to ship internationally via DHL or Fedex. I suspect it would be hard for any healthy person to get a prescription for trametinib from a doctor in the US right now.
Has anyone here every tried shipment from India via Fedex or DHL? How did it work? What was the process / issues?
I had a friend in India ship medications for my father with FEDEX : they just declared the medication involved and it was a 90 day amount. There was no prescription from any US doctor involved. FEDEX cleared customs and charged me (recipient) $20 for customs clearance by credit card before delivery.
But I never repeated it (I was annoyed that FEDEX charged $20 for customs clearance when USPS does it for free) and had the friend use India Postal Service for subsequent shipments.
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I think the difference may be that you had a friend ship it via Fedex (vs. having a company / online pharmacy in India ship them). But since many of these online pharmacies in India are guys working out of their apartments, it is perhaps worth a try⌠doesnât hurt to ask the online pharmacies youâre working with, or considering.
On the Fedex website they say:
https://www.fedex.com/en-il/customer-support/faq/sending/what-goods-can-i-send/send-prescription-drugs-to-us.html
and DHL is pretty much identical:
And I stumbled upon this courier service, but it also requires prescription: Medicine Courier to Usa from India Charges & process| MedsCourier
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Cohen
#91
How many of you are going to start taking low-dose trametinib?
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Bicep
#92
Ha Ha Ha, Not a chance. I was interested in the polyphenol though.
Obvious we really donât know what weâre doing here and itâs a little dangerous and expensive.
cl-user
#93
Iâve added a line showing the average steady state in ng/ml/day:
| Tramedinib Dose (mg) |
Frequency (every X days) |
AUC (ng//day) |
Total 60 day dose |
Percent of Cancer Dosing Level |
| 2 |
1 |
25.597 |
1535.82 |
100.00% |
| 0.5 |
22 |
0.432 |
25.92 |
1.69% |
| 0.25 |
16 |
0.269 |
16.14 |
1.05% |
| 0.125 |
13 |
0.147 |
8.82 |
0.57% |
| 0.125 |
20 |
0.096 |
5.76 |
0.38% |
| 0.0625 |
6 |
0.159 |
9.54 |
0.62% |
Again just a proof of concept.
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Ray1
#95
I might try it a year from now. Mek inhibitors have been shown to reverse intestinal metaplasia in rats and gerbils. There will probably never be a study in humans. I get a 3 year follow up endoscopy of my stomach next year. If the condition has regressed, I will keep doing what I am doing. If the condition is the same or has progressed, Rapamycin plus Trametinib might be worth a try. We will know more by then.
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JosĂŠ
#97
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In the US the âpowderâ form is available, but I believe that its just held at compounding pharmacies and mixed into a solution and put into a bottle at the time of prescription and delivery to a patient (in this case, its designed for pediatric patients) and is a very small percent of the total market.
I canât find any instances of the powder/solution/bottle formulation in India at all (checking on Indiamart) - so I think its very hard to get, especially without a prescription.
So - from what I can tell, it doesnât seem like the powder/oral drink solution is viable right now for the longevity community.
