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.
2 Likes
约瑟夫
#97
2 Likes
In the US the “powder” 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 can’t 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 doesn’t seem like the powder/oral drink solution is viable right now for the longevity community.
约瑟夫
#99
FWIW
Laboratory Trametinib >99%
100mg cost around $100.00
4 Likes
Did you ever try it? ( you were discussing it earlier)
You are right on the lab supply houses, they seem inexpensive, so thats great.
But… for most people its a challenge to order from these sources since they only sell to labs (so you need friends who work in a lab and can purchase this type of compound).
Also the powder needs to be divided into 0.5 mg or smaller dosing, and put into enteric capsules and validate that its actually working (getting into the blood system) as you hope (not getting destroyed in the gut, or pooped out). Without blood tests available for this, its hard to know whether the compound is actually getting into your body and blood.
Example source: Trametinib, >99% | LC Laboratories
@Livin , you had said earlier that “I worked on synthetic lethal chemo combinations in cancer at a startup for years. We tested this compound and it is not a good idea. The Erk pathway is very important for most epithelial cells” in this post Anyone taking Trametinib? - #25 by Livin
But the dosing that they are using in these new longevity studies are at only 1% to 2% (AUC) of the dosing used in cancer studies. What is your evaluation of the risks of trying trametinib in a pulsed dosing scenario as @cl-user has modeled above at the very low doses identified?
Generally, the side effect profile for trametinib at lower doses seems quite good. Last year a pediatric cancer study using dabrafenib and trametinib for over 20 months, suggested “The targeted therapy combination also kept patients’ tumors at bay for longer: a median of 20 months versus 7 months among children in the chemotherapy group”.
Even at these “cancer-therapy” daily dosing levels for 20 months, they found "Among patients taking dabrafenib and trametinib, the most common side effects were fever, headache, and vomiting. Dr. Bouffet described these side effects as “manageable.”
So, from what I’ve read, the risk of taking 98% lower dosing (than used in the cancer treatment clinical trials) seems quite moderate (but I’m not a doctor).
Pediatric Cancer Study using trametinib: https://www.nejm.org/doi/full/10.1056/NEJMoa2303815
6 Likes
Next year (bookmarked #Trametinib2025)
约瑟夫
#103
Reality is…
“If you wait until you are ready, it is almost certainly too late.”
~Seth Godin
2 Likes
约瑟夫
#104
1 Like
With supplements/medications for longevity there are a number of considerations. What is your risk profile for the adverse outcome = 100%. However, how modifiable is the risk profile? How much benefit will you actual realize?
I’d suggest that if you are an obese, smoker, with diabetes, Htn, Hyperlipidemia, vascular and kidney disease like so many of my patients - interventions before irreversible disease occurs can likely yield huge benefits.
If, however, you are at IBW, high quality diet, exercising, good muscle base, insulin sensitivity/BP/lipids all good … the same intervention that might yield the earlier individual a 30% life extension might yield you almost nothing as you may already be maximizing or near maximizing pathways the drug(s)/supplements hit.
This has to be paired with side effects. We have a whole lot of items most of us take that yield essentially no adverse effects, for the majority of individuals. This drug would need careful review for a dose and frequency that would be felt to possibly yield rate of aging benefit, while not causing deaths or significant adverse effects. Another issue is unknown risks with longer term use, as generally this drug is utilized for maximum of a year. We don’t know if use for 30 years will yield any manner of unanticipated bad outcomes.
7 Likes
约瑟夫
#106
FWIW…
We require a “skunk works”
AI-generated answer. Please verify critical facts.
“Testing trametinib serum levels”
Based on the provided information, trametinib serum levels can be quantified using a fully validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method. The lower level of quantification (LLOQ) of this method is 2 ng/mL.
In clinical trials, trametinib serum concentrations were measured to evaluate the relationships between patient characteristics, adverse events (AE), and exposure. Logistic regression was used to compare the risk of treatment discontinuations or dose reductions with corresponding predicted trough concentrations and area under the curve (AUC) of trametinib.
Key Findings:
- No significant relationships were found between dose reduction or discontinuation due to AE and predicted trametinib serum trough concentrations or AUC.
- The lowest p-values were obtained for trametinib dose reduction or discontinuation vs. predicted trametinib trough concentration (p = 0.08) and predicted trametinib AUC (p = 0.10).
Implications:
- Trametinib serum level testing may not be directly correlated with treatment-related toxicities or dose adjustments.
- Further studies are needed to fully understand the relationships between trametinib exposure and clinical outcomes.
Note: The available information does not provide specific guidance on the optimal range or threshold for trametinib serum levels in clinical practice. Consultation with a healthcare professional and review of relevant clinical guidelines are recommended for accurate interpretation and application of trametinib serum level testing.
AI-generated answer. Please verify critical facts.
Learn more.
1 Like
约瑟夫
#107
AI-generated answer.
Please verify critical facts
Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a powerful analytical technique used for the sensitive and selective detection of trametinib in human serum. This method combines the separating power of liquid chromatography with the highly sensitive and selective mass analysis capability of triple quadrupole mass spectrometry.
Key Features:
Simultaneous determination of trametinib in human serum and plasma
Sensitive and selective detection with limits of quantitation (LOQ) and limits of detection (LOD) not specified
Potential application in daily clinical routine for monitoring trametinib levels
Method Development:
The LC-MS/MS method involves a liquid chromatography separation step, followed by tandem mass spectrometry detection. The chromatographic conditions and mass spectrometric parameters are optimized to achieve high sensitivity and selectivity for trametinib.
Validation:
The method has been validated for its accuracy, precision, and sensitivity. The validation process includes the assessment of matrix effects, ion suppression, and the evaluation of the method’s performance characteristics, such as linearity, recovery, and ruggedness.
Conclusion:**
The LC-MS/MS method for trametinib in serum is a reliable and sensitive analytical technique for the detection and quantitation of this kinase inhibitor in human serum. Its application in clinical settings can facilitate the monitoring of trametinib levels and support personalized medicine approaches.
AI-generated answer.
Please verify critical facts
How does this differ from datasatnib which is already in common use as a Q 2 week for 2 day treatment in combination with rapamycin.
1 Like
While their names are somewhat similar, they are very different compounds used in very different applications (and while dasatinib has been identified as a senolytic, trametinib has not).
4 Likes
Sample of pricing on the 0.5 mg tablets, from India.
Trametinib 0.5mg - 30 tablets - 665$ US
Or about $22 per 0.5mg tablet
US Prices:
Or about $163 per 0.5mg tablet.
Source: Mekinist Prices, Coupons, Copay Cards & Patient Assistance - Drugs.com
1 Like
Ludovic
#111
Prices here in Europe are better then in the US, but it’s still a very expensive drug;
1340,96 euros (30 x 0,5 mg).
5109,37 euros (30 x 2 mg).
Unfortunately I don’t want to take the risk of trying to import from India, because an order of Dasatinib from India was confiscated by customs 2 years ago, so this means shipping to my adress gets extra checked and when I try to import medication from abroad again, I will get prosecuted…
1 Like
We can order these drugs in the US. The question is how would we dose the senolytic if it were once every 2 weeks like Datasatnib. Someone suggested 7 mg would be the human dosing equivalent for 60kg man from the study where they gave 2mg daily to the animals.
It would be very hard to get a prescription for this in the USA (its a drug for cancer), and it needs to be refrigerated, so hard to order from India without it being spoiled.
The dosing I calculated where I suggested 7mg was the dosing, was based on a mistake I made at interpreting the 1.44mg/kg as a dose as a function of the weight of the animal. It is actually a dose calculated as a percent of the weight of the food given to the animals - so skip that calculation. It seems the dose we should likely try for humans is in the range of 0.125mg per week, to 0.5mg once every 20 days or so. Since you can’t pill split with this medication (they are coated in a film, we seem to have to use 0.5mg dosing unless there is a way to get the liquid formulation. We need to carefully track to see if there are the same negative effects that are seen at higher dosing.
1 Like
Neo
#114
@RapAdmin i saw @cl-user say that the pills can be split IF combined with enteric capsules
Just wanted to see if you missed that or if you don’t agree with it being an option that could work
My concern around that approach is that we don’t know which enteric capsule is going to replicate the effect of the film coating of the tablets and there is no commercially available blood level test we can use to validate efficacy.
Maybe I am overthinking it, but I would like some way to validate that the capsule approach is working.
It seems to me that the only way we can really be sure that the drug is getting into the bloodstream is if you use the 0.5mg tablet.
1 Like
