The literature seems to support that 3 ng/mL at least has some effect in combination with other drugs to work for organ rejection - below this, not therapeutic. Depending upon the condition, mono-therapy often targets 8-12 ng/mL - and these are trough levels with daily dosing.
We don’t have data on what to do with Rapa for longevity in humans - but I’d suggest that we want to at least be exceeding 3 ng/mL for a couple of days/week with our dosing. Makes sense to me, but no data to support this. Has been safe in my patients thus far.
This often gets into a dose of 8-12 mg weekly for many patients. I don’t tend to go beyond 8 mg without a blood test, or if lower body weight (<150 lbs) above 6 mg without a blood test.
1 Like
adriank
#103
One of my 12 hour blood test came in at 39ng/mL and 36 hour test at 16.9ng/mL. That is 20mg. For that I skip a week. Yesterday I decided to go with 8mg and just managed to get a blood test today at 14.5 hours later. The first nurse had trouble finding my vein. So I’m hoping for greater than 13ng/mL but less than 20ng/mL. What do you think?
I like doing levels at 20-24 hours post dose to make sure everything has redistributed. Folks who are getting a level of ~6.5-7 at that stage probably need to be out on a 10-14 day interval as a reasonable goal is ~30% of the time having mTORC1 inhibition, and 70% of the time in recovery. The levels you are getting will result in significant residual and stacking of doses as your serum level will still be significant at the end of 7 days if dosing that frequently. My concern is that you are under constant mTORC1 inhibition with this regimen. So that brings in all the risks of true immunosuppression.
Talking theoretically here, but that is my thought process, and IF you were my patient, I’d not be advising this type of dosing due to these concerns. To properly map out your T1/2, consider getting a 20-24 hour level, then a repeat in 48 hours after that level. In this fashion, you can have a sense of how long one would have a level >3 … and consider what % of the time you really want significant mTOR inhibition?
I’ve made some arbitrary rules as to how I think things are reasonable. Cannot scientifically support them, as there is no data. But this is my approach to try to maximize benefit and mitigate harms. We’ll know in 40 years if this was sensible.
2 Likes
adriank
#105
My only reason for getting 12 hour and 36 hour blood work is because I take the rapamycin around 10pm at night. No pathology will be open around this time thus the 12 hour and 36 hour interval. Basically at 36 hour if I’m around 6 to 7 ng/mL I’ll stick to the 2 week interval. That is about 8mg with GFJ and I’m about 110kg.
cl-user
#106
If you take only 2 measurements then it’s better to take the first one 24h or more later and the second one 48h after the first one. That will allow you to get an accurate half-life at equilibrium. At 12h you are in the middle of the distribution phase and it’s mostly useless as you don’t know where you are from the intake peak and the equilibrium phase which is the only meaningful phase.
Also be aware that GFJ, Berberine, and other CYP3A4 inhibitors will also slow the clearance in a non linear way over time if you only take one shot of GFJ.
4 Likes
You might want to take your Rapa in the AM the rare times you check a level. However, knowing at 36 hrs you’re are at 6-7 usually means you’ll have 2 days or so >3 beyond that, so you’d be looking at 3.5 days of pretty solid levels >3, maybe 4 days … so every 2 weeks would be a reasonable approach if buying in to my randomly made up theories.
3 Likes
cl-user
#108
@adriank says that he uses GFJ so that will significantly increase the half-life time and he most probably still have a meaningful amount of rapa at 1 week.
For instance I don’t use GFJ because it’s too unpredictable mostly for the equilibrium phase, as the CYP3A4 inhibition will wane over a few days, which means the half-life will start high then gets lower as rapa clearance increases.
That said I do take 2x400mg of berberine each day which is also a CYP3A4 inhibitor but, as I take it every day, that amount of inhibition is constant and so is the half life so it’s possible to have consistent and predictable levels. In my case the half life with berberine is 82.5 hours which is much more than the standard 62h.
Anyway I totally agree with you that 2 weeks is much safer in that case and more generally for anybody using GFJ, berberine, etc
1 Like
I haven’t received link to today’s Pearl webinar. Thought I did register but haven’t received anything yet. Starts in 15 min!
1 Like
It was confusing… they didn’t email us the link, you had to be logged into EventBright and they showed the link to the zoom call. It was 1pm Eastern time - so it took place already. They’ll post the video on YouTube - so not a big deal if you missed it.
4 Likes
Neo
#111
Any key takeaways other than the ones we have discussed here over the last few days since the preprint came out?
1 Like
Agetron
#112
I did listen… don’t think I really brought away anything new.
Perked up to the part where Matt Kaeberlein talked about dosing protocols (and gave several shameless self-promotions for his Optispan podcasts - lol), and that the trial really didn’t give any dosing discoveries. Can go one way or the other. That what he continues to believe is that everyone is a little different, and therefore the dosing for one person might be different from others. Also a bit on dosing for men and women.
The fact that they didn’t have good biological markers for any changes surprised me because I would think that with the glycans, you could actually measure inflammation differences, and that to me is key to aging?
When they mentioned using GlycanAge, they didn’t have much information. Possibly because only about forty participants had any interest in doing that test. Therefore they didn’t do it…nor have any real data… was my take away. REALLY?
All in all I think Kaeberlein said you’d likely get at least ten extra years using rapamycin… that was said a few times in different ways.
5 Likes
I tend to think that the results were in the meh category which is not surprising for a dose o either 1.5 or 3mg of generic equivalent. Personally i think the highest concentration is more important than aggregate AUC for benefits.
5 Likes
adriank
#114
Why not I just get a test at 3.5 days. If it is still over 3 then I’m good.
adriank
#115
I believe I can make the generic work the same. Just by having it a few hours after meals to reduce the impact of the digestive acid
2 Likes
The point about the trial is that generic has enteric protection and is more bioavailable than compounded. (ABT 3X)
2 Likes
I haven’t had a chance to listen yet, but I hope to hear subsequent data on the periodontal, blood lipid and body fat effects. Did they touch on any of that?
adriank
#118
This week I took 8mg. My serum at 14 hours is 9.3ng/mL. I have just taken another test at 85 hours (3.5 days). Based on the half life if 63 hours it is safe to say that it should be greater than 3ng/mL. Anyway beginning of next week I’ll have the result. BTW how did you come up with 3ng/mL as the target for 3 to 4 days? Can you provide me with a reference? Thx you.
Just got my results for 85 hours. It is 2.9ng/mL.
My Biocon is still with customs. When it comes in I’ll try 8mg and see if it is the same or stronger.
1 Like
I very much agree with this.
3 Likes
That’s not what happens. GFJ almost exclusively effects CYP3A4 in the intestines not the liver so it will increase absorption but is unlikely to significantly slow down breakdown in the liver.
3 Likes
DrFraser
#121
I agree with this. I’ve got at least a bit of data on those taking with GFJ vs. Not, and I don’t see a significant or consistent change in the half life, but a big bump up in the level at 20-24 hrs if taken with GFJ, which I’ve typically been having people do 8 oz, 3 hrs before Rapamycin, then 4 oz with it - and make sure it is good quality and stick with the same brand in order to expect a somewhat consistent result. Also make sure one isn’t on other drugs affected by CYP3A4.
AI correctly details this effect - here is a copy/paste.
Grapefruit juice can inhibit the cytochrome P-450 3A4 (CYP3A4) enzyme in the small intestine, which can cause adverse effects when taken with certain medications:
Grapefruit juice blocks the action of CYP3A4, which metabolizes many drugs. This means that more of the drug enters the blood and stays in the body longer, potentially leading to too much of the drug in the system.
Grapefruit juice can affect many drugs, including cyclosporine, some 1,4-dihydropyridine calcium antagonists, and some 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors.
- How much grapefruit juice is needed
As little as one whole grapefruit or 200 mL of grapefruit juice can cause clinically relevant effects.
- How long the effects last
The effects of grapefruit juice on CYP3A4 can be measured for up to 24 hours after consumption.
The inhibitory effect of grapefruit juice is mainly due to furanocoumarins, which are naturally present in the fruit.
5 Likes
