From the Mannick paper.
“In the intent-to-treat population, the low-dose RAD001 (0.5 mg daily or 5 mg weekly) cohorts, but not the higher-dose (20 mg weekly) cohort, met the primary endpoint of the study”
Some more insight from this paper on our dosing regiments/mTOR inhibition discussion:
"Modelling and simulation based on mTOR-mediated phosphorylation of its downstream target S6 kinase (S6K) predicted that the 20 mg weekly dosing regimen inhibited mTOR-mediated S6K phosphorylation almost completely, the 5 mg weekly dosing regimen inhibited S6K phosphorylation by more than 50%, and the 0.5 mg daily dosing regimen inhibited S6K phosphorylation by about 38% over the dosing interval (12). Thus, partial inhibition of mTOR-mediated S6K phosphorylation achieved with a relatively low dose of RAD001 may be as effective as nearly complete inhibition associated with high-dose RAD001 at enhancing the immune response of the elderly volunteers."
If you look up the reference 12, where the modelling is for CANCER (hmmm…they basically lifted a cancer model and used for the immuno study):
https://sci-hub.se/10.1200/JCO.2007.14.1127
“Inhibition of S6 kinase 1 (S6K1), a molecular marker of mTOR signaling, was selected for PD
analysis in peripheral blood mononuclear cells (PBMCs) in a phase I clinical trial. PK and PD were measured up to 11 days after the fourth weekly dose. A PK/PD model was used to describe the relationship between everolimus concentrations and S6K1 inhibition in PBMCs of cancer patients and in PBMCs and tumors of everolimus-treated CA20948 pancreatic tumor–bearing rats.”
“Comparison of rat and human profiles simulated by the model suggested that a weekly 20- to 30-mg dose of everolimus would be associated with an antitumor effect in an everolimus-sensitive tumor and that daily administration would exert a GREATER effect than weekly administration at higher doses”
For Everolimus:
“This PK/PDmodel of S6K1inhibition has, therefore, provided an indication of which doses and regimens should be investigated clinically, starting at 20 to 30 mg/wk and 5 mg/d, respectively. The model predicts that such doses might inhibit the molecular target sufficiently to exert anticancer effects”
So there you go…one data point on daily vs weekly on a mTOR inhibition pathway of cancer.
You can see the S6K1 inhibition pharmacokinetics (daily vs weekly) in the lower 2 graphs in the image below. Rapamycin would of course have a different graph, but conceptually similar.
You can also see how Cmax is important for IC50, depending on tumour cell line. Intermittent dosing keeps hitting tumour cells with greater sustained IC50 via higher Cmax pulses.
It’s pretty to clear to me why pretty much every cancer/transplant study…dosing is daily to maximize cancer inhibition, and side effects…as “much as can be tolerated”
