Some very good results (significant reduction of side effects) from intermittent dosing of trametinib:
Intermittent dosing in these examples is defined as: a five-week-on and three-week-off schedule.
In February 2016, after almost a full year of continuous daily dosing, she started a 3-week drug holiday before resuming treatment using an intermittent schedule of 5 weeks of treatment followed by a 3-week break, per 8-week cycle. This approach was associated with a considerable reduction in her fatigue and an improvement of her well-being.
Like patient 2, this patient noted considerable improvement in her sense of well-being after converting to an intermittent therapy regimen. On treatment for now 18 months (13 months on intermittent drug administration), this patient continues to tolerate dabrafenib and trametinib at full dose on the five-week-on, three-week-off schedule and has resumed work unencumbered by symptoms from her disease or from the treatment.
Both patients experienced considerably fewer adverse events and no cumulative toxicity with intermittent dosing, permitting them to resume active lifestyles largely unencumbered by the anticancer treatment.
Results: Both patients showed rapid clinical improvement upon starting the regimen. They also noted improved tolerance of treatment upon transitioning to the intermittent dosing schedule. They continue to show evidence of antitumor activity 27 and 18 months respectively from the start of treatment and 15 and 13 months respectively from the start of the first break using intermittent dosing.
Intermittent Dosing of Dabrafenib and Trametinib in Metastatic BRAFV600E Mutated Papillary Thyroid Cancer: Two Case Reports
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Here is a phase 2 clinical trial looking at intermittent dosing with trametinib:
Continuous versus intermittent BRAF and MEK inhibition in patients with BRAF-mutated melanoma: a randomized phase 2 trial
The intermittent dosing arm used the same doses during weeks 1 and 5ā8 of each 8-week cycle (5 weeks on). No therapy was given during weeks 2ā4 on the intermittent therapy arm (3 weeks off).
Adverse events.
All adverse events assessed as possibly, probably, and definitely related to study treatment. On the continuous therapy arm, 38 patients (36%) experienced grade 3 adverse events, and 7 (7%) experienced grade 4 events, while on the intermittent therapy arm, 31 patients (31%) experienced grade 3 adverse events, and 3 (3%) experienced grade 4 events (p=0.46 for grade 3, p=0.33 for grade 4). The most common grade 3ā4 adverse event across both arms was fatigue. There was a significant difference in the incidence of grade 3 and 4 pyrexia, (6 patients on continuous dosing vs 1 patient on intermittent dosing, p<0.001).
There has been at least one additional (2024) clinical study using intermittent dosing schedules, and larger numbers of patients, for trametinib, but it is behind a paywall. If anyone can access and post it please do, as it would give us more information on the side effect reduction from continuous to intermittent dosing schedules.
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I donāt think there is any hurryā¦ weāre all going to get some extra time from the rapamycin, and it seems some de-risking could and should be done by longevity researchers on trametinib before even periodic dosing is tested by biohackers:
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Good points. Best to avoid for now.
Cohen
#39
The half-life is also long, so you can take it once a week or every two weeks without any hassle.
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nikney
#40
The half-life of trametinib is 4-5 days, almost twice as long as rapamycin. If you take rapamycin every day, you may experience a lot of side effects. But once a week, it causes almost no side effects. Couldnāt a similar situation occur for trametinib taken once every two weeks? Since no one has tried it, we naturally have no information. But I think there is an unnecessary fear about this.
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There is definitely a reasonable argument that dosing once every week or two with trametinib could have very low or minimal side effects, but it would be good for a medical group to do such a test with regular blood and functional monitoring for the more serious potential risks; retinal issues, heart issues (ejection fraction), blood pressure, kidney function, anemia, etcā¦ It would be very hard, if not impossible, for a biohacker to be able to do this type of monitoring over a period of many weeks or months, so I really think we need to lobby a longevity research group to start a small clinical study to do this, and publish the results.
@Livin and @Vlasko , given your experience with, and knowledge about, this drug what are you opinions? How would you design a study to test its safety in a pulsed once weekly or once every two week dosing schedule?
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KarlT
#42
We could use a few human test subjects if youāre volunteering?
Cohen
#43
And whoās going to pay for the trial?
Iām going to write up a proposal, try to get some researcherās to partner with, then submit a the idea to Impetus Grants. Iāll post the proposal here to get peopleās feedback on it before I approach the researchers.
What Iām proposing is effectively a new phase 1 clinical study (perhaps a dozen participants or so). Iād be following this type of guideline: A Comprehensive Guide to Phase 1 Clinical Trials
It seems like a small phase 1 clinical study like this with a commercially available, FDA-approved drug, might cost something like $200K to $300K; similar to the dental rapamycin study: New Study Funded: Towards reversing periodontal disease using Rapamycin
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And, more good news on trametinib; it appears it goes off patent in 2025, so at that point it becomes very inexpensive.
Trametinib (Mekinist)
Like dabrafenib, trametinib is used against melanomas containing the activating BRAF V600E or V600K point mutation [44]. It was authorized by EMA in June 2014 and the EU patent is expected to last until July 2029. However, trametinib was authorized by FDA in May 2013 and the patent is expected to expire in September 2025, resulting in three years less market exclusivity in the US.
Source: Overview of the patent expiry of (non-)tyrosine kinase inhibitors approved for clinical use in the EU and the US - GaBI Journal
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Maybe it would be a good ITP candidate for verification?
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I donāt believe there is any evidence that low-dose Trametinib has a significant life extending effect which is the main issue for this. Would it be possible perhaps to try a low-dose Trametinib trial in the wormbot?
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See the earlier post by @Cohen
I also just realized I mis-interpreted the 1.44mg/kg as per kg of weight of the mouse, whereas its actually a measure of drug in the food.
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Gokhan
#49
Dosing to match mice plasma levels
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The lifespan-extending dose of trametinib (1.44 mg/kg diet) resulted in plasma levels of ~0.1 ng/ml in mice. This is significantly lower than the 5.5-7.5 ng/ml peak levels observed in human patients receiving 2 mg daily doses for cancer treatment. [1]
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Considering trametinibās long elimination half-life of 3.9 to 4.8 days in humans, an appropriate starting dose for human longevity trials might be 0.25-0.5 mg taken orally once or twice weekly. This weekly dose, approximately 1/8th-1/4th of the standard 2 mg daily dose used in cancer treatment, aims to maintain plasma levels similar to those observed in the long-lived mice (around 0.1-0.2 ng/ml) while accounting for the drugās extended presence in the body.
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Trametinib is sold in 0.5mg tablets. A single 0.5mg tablet can be obtained for $21 in a country like Turkey. If one were to use 0.5mg weekly, the yearly cost of the drug would be $1100.
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We can follow the same principle that Dr Blagosklonny has long proposed for Rapa: The optimal longevity dose is the highest dose without side effects.
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As an experiment, Trametinib timing can be aligned with intermittent Rapamycin timing to maximize the āfasting-likeā effects (two nutrient sensing pathways blocked simultaneously).
[1] A combination of the geroprotectors trametinib and rapamycin is more effective than either drug alone, Gkioni et al, 2024 (preprint)
Trametinib user experience (Link)
- 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
(Not Mine ā From another Rapamycin group. Sharing because itās very interesting!)
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Gokhan
#50
Triple Drug Combination Targeting Nutrient-Sensing Network Dramatically Extends Lifespan in Fruit Flies (2019)
This study investigated the effects of combining three drugs that target different components of the nutrient-sensing network to extend lifespan in fruit flies. The researchers tested rapamycin (an mTOR inhibitor), trametinib (a MEK inhibitor), and lithium (a GSK-3 inhibitor) individually and in combination. They found that double combinations of these drugs produced greater lifespan extension (around 30% on average) compared to any single drug alone (11% on average). Most remarkably, the triple combination of all three drugs extended median lifespan by 48%. The drug combinations did not significantly alter feeding behavior or food intake, suggesting the lifespan effects were not due to dietary restriction.
Importantly, the study also found that lithium was able to counteract some negative side effects of the other drugs. Specifically, lithium reversed the increased triglyceride levels and starvation resistance caused by rapamycin treatment. The researchers conclude that simultaneously targeting multiple nodes of the nutrient-sensing network with drug combinations may be an effective strategy to maximize longevity benefits while minimizing side effects. They suggest this āpolypharmacologyā approach of combining established pro-longevity drugs could potentially be developed into therapies to improve health in late life.
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Gokhan
#51
Targeting RAS/MAPK Signaling: A Promising Approach for Extending Healthspan and Lifespan (2022)
This review examines evidence that inhibition of the RAS/MAPK signaling pathway can extend lifespan and improve healthspan across multiple model organisms. Genetic studies in yeast, worms, flies and mice have shown that reducing activity of various components of the RAS/MAPK pathway can increase lifespan and enhance resistance to age-related decline. The effects appear to be evolutionarily conserved, as variants in human RAS pathway genes have also been associated with longevity. The RAS/MAPK pathway integrates with insulin/IGF signaling, a well-established aging regulatory pathway, suggesting it may be a key node in controlling the aging process.
Based on these genetic findings, the authors discuss the potential for repurposing existing RAS/MAPK inhibitor drugs as āgeroprotectorsā to promote healthy aging in humans. Several compounds that directly or indirectly inhibit RAS/MAPK signaling, including trametinib, statins, acarbose, and metformin, have shown lifespan-extending and health-promoting effects in model organisms. However, challenges remain in translating these findings to humans, including potential side effects and the need to determine optimal dosing and timing of interventions. Nevertheless, the authors argue that pharmacological modulation of RAS/MAPK signaling represents a promising avenue for developing interventions to extend healthspan and lifespan in humans.
Trametinib: RAS/MAPK/ERK Signaling Pathways and Mechanism of Action
signaling pathways
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I wanted to add this comment from @Ray1 here, as its relevant. Just as with rapamycin, the general perception of medical professionals (given the typical cancer dosing levels used with trametinib) is quite negative. This suggests that, just as with rapamycin, getting an IRB approval for study in healthy humans may be a challengeā¦ but, weāll see.
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jnorm
#53
Warning: mechanistic speculation aheadā¦ 
Chronic rapa (for 4 mo or 16mo) in male mice can oppose the increased ERK activation that normally occurs during that time frame in liver and kidney. So itās not actually reducing ERK activation below the level present in young miceājust preventing the age-associated increase.
Even if we can just maintain youthful levels of ERK activation, I think that is huge. Because ERK is one of the primary positive regulators of AP-1 activity. AP-1 is a transcription factor recently shown to be a master regulator of epigenetic remodeling in aging. Presumably more ERK activity->more AP-1 activity->more rapid loss of epigenetic information
To get ERK below even youthful values, you could periodically pulse a bona fide MEK or ERK inhibitor.
Another alternative to trametinib would be function-selective (as opposed to ATP-competitive) ERK inhibitors like SF-3-030, which affects expression of fewer genes than ATP-competitive ERK inhibitors.
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