In this study they were taking rapamycin at a level as high as 90mg/week for cancer.
“The most common toxicities attributed to sirolimus observed throughout all three studies were hyperglycemia, hyperlipidemia, lymphopenia, anemia, and diarrhea. In the sirolimus alone study, the single weekly dose of 60 mg was associated with significant diarrhea and gastrointestinal upset so subsequent cohorts were administered split doses”
Gastrointestinal toxicity on the split dose level consisted of diarrhea, nausea, and emesis. These were managed conservatively with antidiarrheals (loperamide or diphenoxylate/atropine as needed) and antiemetics. All subjects were able to continue therapy although one required dose interruption due to diarrhea.
A single cycle of treatment was defined as 4 consecutive weeks with no scheduled interruptions between treatment cycles. A minimum of 8 consecutive weeks (2 cycles) was administered before re-evaluation of disease status.
The highest dose levels in both studies exceeded our minimal target AUC goal of 3810 ng-hr/ml. When sirolimus was administered alone, gastrointestinal toxicity necessitated splitting the dose into two equal administrations. Although five subjects were accrued to the 45 mg-24 hours apart dose level, only two subjects were evaluable for pharmacokinetic analysis. Data from this cohort suggested that a 90 mg total weekly dose would achieve AUC close to the target, and thus accrual to the sirolimus alone study was stopped.
Sirolimus is commercially available with a safety record much longer than any of its analogues. Moreover, the patents for sirolimus for most oncology uses have expired, and thus the potential exists for substantial cost savings over its analogues. Therefore, sirolimus represents a viable cancer drug whose development would offer several advantages with further cost savings realized by combining the drug with agents that inhibit its metabolism.
Interesting! I found this study on in vivo and the successful dosages was between 5–20 mg/kg daily.
We showed, in our study, sirolimus significantly inhibits tumor growth at all dosages (5–20 mg/kg) compared to control … In the minimal residual disease model, sirolimus slowed the growth of tumors and increased survival … We found that final tumor volumes were relatively similar in the establised tumor model, despite increasing dosages of the drug at 5, 10, 15 and 20 mg/kg. This suggests that higher dosages of sirolimus may not provide any additional benefit in preventing HNSCC tumor growth. … Our data also suggests that a 7 day/week treatment regimen may produce better outcomes than a 5 day/week regimen.
Here is one study on Everolimus with quite low doses
(Everolimus) used also as anti-rejection agent for transplantation but with lower doses for anti-rejection (1.5-3.0 mg/day) than for anti-cancer (5-10 mg/day) treatment.
Is there any way to convert the Everolimus dose in mg to Sirolimus dose?
If I try to convert it from the usual doses on anti-rejection on Sirolimus (2 - 5 mg/day) than the anti-cancer dose for Sirolimus equal to Everolimus would be around 7,5 - 15 mg/day. Is that right or is there a better way of converting a dose from Everolimus to Sirolimus?
When I look at the study above with a Sirolimus dose of 90mg/weekly if we see what the dose of that is on average per day it’s 12,85mg/day. This is good aligned with calculated dose interval 7,5 - 15 mg/day.
It’s hard to conclude that the conversion factor between Sirolimus and Everolimus are but the dose of Everolimus is likely higher than Sirolimus in most cases and in some case it can probably be equal.
Nice that you hade the Lloyd Klickstein interview there because that was one place I would also look at. In the study they discuss they use both Temsirolimus and Everolimus and not Sirolimus. I wonder if he is talking about Temsirolimus in this context than Sirolimus.