A Combination of Rapamycin and Trametinib Extended Maximum Lifespan by up to 35%

[nikney]

It seems that the mapk pathway even affects the circadian rate. It is interesting that the circadian rate is also linked to these pathways. We learn new things every day. Gerontology is advancing very quickly. It also says in this article that trametinib reverses gray hair. Trametinib is on its way to becoming the new rapamycin.

[KarlT]

@Gokhan

In 2020 I ran trametinib in 2 separate experiments. I was forced to discontinue quickly due to notable unpleasant side effects.

I figured someone here would be crazy enough to try this.

[RapAdmin]

@Gokhan

Trametinib User Experience

• In 2020 I ran trametinib in 2 separate experiments. I was forced to discontinue quickly due to notable unpleasant side effects.
• Dose: 1mg/day
• This was based on studies showing triple combo of rapa lithium tranetinib extending life close to 50%. I had calculated 4mg/day [based on the fruit fly study] and started light to be safe. Maybe I got it wrong?? Took a few days to feel like shit.
• What were the side effects? feeling poisoned. drained. off

Thanks for posting your experience! Obviously daily dosing at this level is probably not optimal for longevity.

But perhaps 0.5 mg/week or 1mg/week or even 2mg/week may provide the benefit without the side effects. Do you have any of the medication left, and perhaps you could try a dosing schedule more similar to this?

I’m talking to researchers about a phase 1 clinical trial for safety of low dose trametinib in healthy humans, and one person also suggested “you can also consider an observational trial or case series as a first step”.

I checked on pricing from India. Current pricing for Trametinib (2 mg tablets) is $4,500 / 60 tablets (or $37.5 US per mg).

If generics become available quickly after the drug goes generic in the US (Sept/2025), then prices should drop to around rapamycin prices of $1 to $2 per mg.

[AnUser]

@RapAdmin

But perhaps 0.5 mg/week or 1mg/week or even 2mg/week may provide the benefit without the side effects.

The therapeutic index for longevity might be much lower and the dose used in cancer is actually the toxic dose (FYI I don’t know anything about this compound).

[RapAdmin]

Yes - that is what the Partridge lab people are saying (lower doses for longevity).

So - I’ve been digging around trying to find the original dosing studies to see what data we can get on these lower doses and how they translate into blood levels, that we can then compare to the new paper from the Partridge lab.

I’ve found this:

Dose selection for phase II and III clinical trials with trametinib was based on the results from its phase I study in which daily doses ranging from 0.125 to 4 mg were administered to patients with solid tumors.

So - this would seem to be the data we want to look at. We want to see if the lowest level of drug dosing used in this phase 1 dosing study might meet the blood level dosing requirements for longevity that we see in the new longevity study from the Partridge lab, and then check on the side effect profile of these very low doses to see if they might work (be tolerable) for most healthy people.

Looking through the original FDA approval package for the drug, I think the original phase 1 dosing study is of most interest because it covered a range of lower doses.

So I’ve found the original FDA study information filed in 2013 that was generated from this original Phase 1 clinical study.

Here is the original clinical study overview: ClinicalTrials.gov

And the data repositories now: https://www.clinicalstudydatarequest.com/Posting.aspx?ID=519&GroupID=DEFAULT

Which then brought me to this site where the actual reports are:

https://www.gsk-studyregister.com/en/trial-details/?id=MEK111054

At the bottom of the page are two sections under the “Study Documents” section (note the Clinical Study report is a 56MB document with over 2700 pages of information, and the Scientific Results only 5MB):

Clinical Study Report

Scientific Result Summary

I’m very interested in the 0.125mg dosing, the 0.250mg, and the 0.5mg dosing levels and resulting blood levels and curve.

Reviewing the clinical study report, I see the following:

Lots of interesting information here, but a ton of data to dig through, and then compare to the new paper data. I’m working on it.

Feedback and thoughts from the medical professionals that participate here, on this data is of course always greatly appreciated.

[RapAdmin]

Following is the paper that they published on that Phase 1 dosing escalation study. Safety, pharmacokinetic, pharmacodynamic, and efficacy data for the oral MEK inhibitor trametinib: a phase 1 dose-escalation trial - PubMed

The good news is that there doesn’t seem to have been much in the way of side effects seen until they got above the 1.0 mg dosing level (this was a 21 day dosing study, daily dosing). So it’s increasingly looking like low dose longevity use may be viable.

infante2012-2.pdf (245.9 KB)

[tananth]

From the plots it looks like even a single dose of 0.5mg results in plasma concentration of 0.3 ng/mL after 2 days, 3x the targeted level of 0.1ng/mL in the mouse study. This means a dose of 0.25mg once weekly should be more than enough to achieve an average level of 0.1ng/mL.

[RapAdmin]

Yes, but the data seems a little sketchy… the “Cmax” for 0.125 mg is higher than that for 0.25mg dosing, and both are N=1, so it seems there is a high level of interpersonal variability (and I can’t believe they used N=1 at this lower level… really, GSK, this is the best you can do in this phase 1 dosing study?).

So there are going to be some pretty large error bars around those “Cmax” measures.

But overall, yes, its looking like people could get by taking a pretty low dose of trametinib to meet the longevity blood levels suggested in the most recent paper. And, trametinib is sold in 0.5mg tablets as well as 2mg tablets, so it would be easy to split the 0.5mg tablets into 2 or 4 pieces.

[RapAdmin]

I’m trying to pull the key information out of the 2,700 page clinical study file that GSK has helpfully provided. Below I think are some of the key points of information and graphs… I’m hoping that @cl-user might be able to help us and graph the dosing schedule and blood levels given the target blood levels provided in the recent paper (0.1 ng/mL), half-life of around 90 hours, the data I posted earlier, and the data below…

[Gokhan]

Hi! Please note that I was relaying the experience of a Rapamycin Facebook group user. You can go to the linked thread to contact him and ask any detailed questions.

[cl-user]

Here it is. I can make use the model to Make dosage simulations if you want.
That said the quality of initial trial data is very poor and the model is only based on that.

BTW please note that, similarly to rapamycin, the peak height is meaningless as it only shows the difference of speed between GI absorption and distribution to the organs. Reducing the absorption speed will reduce the peak height but end up with more trametinib into the organs.

I can also use other thresholds than 1 and 3ng/dl.

[tananth]

The right bottom plot shows that average plasma concentration from daily dosage of 0.125mg seems to be around 0.7 ng/mL. These daily dosing charts look less noisy than the single dosing charts.

This suggests that to achieve an average level of 0.1ng/mL, you need a weekly dosage of 0.125mg , though the plasma level won’t be as uniform with weekly dosage of 0.125mg as it would with daily dosing of 0.125/7 mg, but it is at least possible to divide a 0.5mg tablet into 4 weekly 0.125mg pieces.

[cl-user]

Here is the simulation for 0.25mg daily

And 0.125mg every other day

[RapAdmin]

In the Glaxo documents, and other studies, they talk about the half-life being around 90 hours. Why is the “blood half life 4.81 h” in your graphs?

The target suggested in the new longevity pre-print paper is a blood level of trametinib of between 0.1 ng/ml, and 0.2 ng/ml. What dosing level and frequency do you think provides roughly that level over longer period of time?

[cl-user]

@RapAdmin

Why is the “blood half life 4.81 h” in your graphs?

It’s 48.1h. In the report table the half-file is 48.8h for 4mg and I used the 10mg data for the model fit as the points are better.

That said the half-life is all over the place and seems to be very long at low doses. For instance they don’t give any half-life for 0.125mg and 0.25mg, 1 individual at 161h for 0.5mg, 291h and 121h for 1mg.
That’s not really actionable. 291 is more than 12 days while 121 is 5 days.
The largest interval is for 2.5mg where the confidence interval goes from 4h to 210h.
If you have some strong feelings about a value for the low dose half-life, I will use it to find the optimal dosage.
Here is what we get with a 161h half-life

Same dosage but 291h half-life ends up with twice the concentration

[RapAdmin]

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.

[RapAdmin]

@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?

[cl-user]

@RapAdmin

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 it’s 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.

It’s 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)

[RapAdmin]

Ok, I’ve 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 doesn’t seem that the tablets can be split / divided.

The tablets are film coated, and everywhere I’ve 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 I’ve 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 I’ve seen that have driven me towards this conclusion:

Sources:

• https://www.medicines.org.uk/emc/product/5072/smpc
• Pill splitting - Is it safe?

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 – 4AllFamily

Source: Mekinist: Uses, dosage, side effects, cost, and more

[Neo]

@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

Monitoring of Dabrafenib and Trametinib in Serum and Self-Sampled Capillary...

Phase I pharmacokinetic study of single agent trametinib in patients with advanced cancer and hepatic dysfunction

Phase I pharmacokinetic study of single agent trametinib in patients with...