Appears you believe 6mg/week is bioequivalent to 1mg/day…absolutely NOT. The pharmacology of biodistribution and pharmacokinetics are highly non linear. With the rapid peak and 62 hr half life, daily dosing will fundamentally alter the balance between absorption and clearance. 1mg/day is a VERY potent dose.
Dr Green: “The side effects of daily rapamycin are TOTALLY different from the side-effects of weekly rapamycin. Daily rapamycin is used to reduce both mTORCl and mTORC2. Reduction of mTORC2 has significant side-effects. Almost all the harmful side-effects of rapamycin use are from lowering mTORC2 and all the beneficial anti-aging effects are from lowering mTORC1.”
We already know this from the work of Lamming, etc. While studies show this, and clinical translation quasi confirms (have we ever seen measurement of mTOR1 and mTOR2 in humans?..NOT), this is NOT to say that the right daily dose cannot produce a better AUC/biomarkers/side effect profile, the purpose of your exploratory protocol. It’s all in the dose.
A Phase 1 dose-finding and pharmacodynamic study of rapamycin in combination with bevacizumab in patients with unresectable hepatocellular carcinoma
https://sci-hub.se/10.1016/j.ejca.2012.11.008
“First, prior studies evaluating sirolimus pharmacokinetics have suggested a linear relationship between dose delivered and AUC (47, 48). In our study, a nearly 7-fold increase in AUC was seen after doubling the dose from 0.5mg/week to 1 mg/week.”
In the graph below you can see that doubling rapamycin from 1mg/day to 2mg/day produces a far higher than 2X increase in trough and AUC. And even 1mg/day can produce trough above 5 ug/L.
And the ADE of 1mg/day:
“The antiangiogenic and immunosuppressive effects of rapamycin are mediated by the drug’s effect on endothelial cells and lymphocytes, respectively. Cmin may not be a good indicator of the drug exposure in endothelial cells compared to AUC0–inf or dose. Hence, AUC0–inf or dose
may be more suitable biomarkers of the antiangiogenic effect of rapamycin”
Phase I Trial of Encapsulated Rapamycin in Patients with Prostate Cancer Under Active Surveillance to Prevent Progression
Cohort 3 in the image below is 0.5mg/DAY rapamycin. The range and level of ADE and DLT is far higher than the mathematical equivalency of say 3.5mg/week (7 x 0.5mg/day). Most people and studies I’ve seen, 3.5mg/week has very little impact (population level). Yet, 0.5mg/DAY is quite potent already. They didn’t measure and/or report any lipid or glucose markers.
“The impact of rapamycin on tumor cell proliferation is also likely secondary to modulation of the immune system, a process that would require a longer treatment period than 2 weeks in both in vivo and clinical studies to reduce immune exhaustion and senescence while stimulating an effector response.”
Immunologic effects
“Immunologic data were available for all patients in cohorts 1 (0.5mg/WEEK) and 2 (1mg/WEEK) at each specified timepoint. In cohort 3 (0.5mg/DAY), samples were collected from all patients (n ¼ 8) at baseline, from 7 patients at the 1-month timepoint, and from 5 patients at the 3- and
6-month timepoints. Weekly dosing (cohorts 1 and 2) tended to increase na€ve cell populations and reduce central memory cells, while daily dosing (cohort 3) tended to maintain markers
of central memory”
“The 0.5 mg daily dose, which resulted in the highest cumulative total dose per week of each of the dosing regimens studied, produced a higher degree of mild toxicity and a transient negative impact on QoL”
IF you have a good steady state baseline of 6 mg/week re side effects, biomarkers, trough level Sirolimus, then I’d suggest perhaps starting with 0.5mg/day, and let it run for longer than 2-3 weeks before you take new markers. You are n=1, and your results may be quite different than studies referenced capturing 0.5mg/day or 1mg/day. Perhaps start with 1mg/day and see how it goes, but if you really start to feel like crap, then perhaps back off to 0.5mg/day, and let that run.
Other than biomarkers and side effects, you of course will never be able to assess long term impact (lifespan), but you might be able to titrate closer towards Dr B’s theory of “taking as much as you can without side effects”, which is as good as any human translation goal post. And “as much as you can” meaning, this might implicitly translate to AUC. If you an increase your AUC and not negatively impact long term biomarkers (lipids/glucose, WBC, etc)/ADE, a potentially positive outcome. A worthwhile n=1 experiment!
