Rapamycin (Sirolimus) What to Expect, Week-by-Week First Month

Is there a week-by-week pattern to the first month?

The published human trials of low-dose rapamycin give results for a whole treatment period, not a weekly diary. The PEARL trial followed healthy, normative-aging adults for 48 weeks on placebo or 5 mg or 10 mg of compounded rapamycin taken once weekly, and reported that adverse and serious adverse events were similar across all groups [1]. A smaller pilot randomized 25 generally healthy adults aged 70 to 95 to 1 mg of rapamycin daily or placebo, with 11 rapamycin and 14 placebo participants completing at least 8 weeks [3].

The reaction rates printed in the Rapamune label come from different settings again: 12-month kidney transplant studies at 2 mg and 5 mg per day, and a trial in lymphangioleiomyomatosis (LAM) in which the initial dose was 2 mg per day [2]. The label notes that adverse reactions were generally dose- and concentration-dependent [2]. Weekly low-dose use sits outside those labeled settings, so any week-by-week account of it is extrapolation rather than observation.

The Rapamune label says to take the product once daily, consistently with or without food, and says tablets should not be crushed, chewed or split [2]. The label describes no weekly schedule.

Week 1: how long a dose stays in the body

Sirolimus has a mean terminal half-life of about 62 hours (SD 16) in stable kidney transplant patients, and 91% of radioactivity is recovered in the feces [2]. A week is a little under three half-lives, so some drug remains when the next weekly dose is due.

The PEARL abstract reports 48-week outcomes. Visceral adiposity measured by DXA did not change (p=0.942) and blood biomarkers stayed within normal ranges [1]. Self-reported emotional well-being and general health improved in the 5 mg group, and lean tissue mass and self-reported pain improved in women on 10 mg. These are results from a 48-week trial, not first-week effects [1].

Weeks 2 to 4: the reactions the label lists

Stomatitis is a labeled reaction. It appears in the label's 20%-or-more list from the LAM trial, and in the 3%-to-under-20% list for kidney transplant patients [2]. Diarrhea, nausea and abdominal pain are also in the common lists, and acne appears in the LAM list at 20% or more [2]. In the transplant table, rash occurred in 20% of patients on 5 mg per day versus 6% on placebo [2].

The 25-person pilot reported what a small group experienced. In the rapamycin arm, side effects were a facial rash in one participant, stomatitis in one, and gastrointestinal issues in two [3]. That study also found statistically significant decreases in hemoglobin, hematocrit, red cell count, RDW, MCV and MCH in the rapamycin group [3].

Interstitial lung disease is a labeled risk of sirolimus and is listed among the warnings and precautions [2]. A case series described eight kidney transplant recipients who developed unexplained interstitial pneumonitis during sirolimus therapy. Their clinical and radiological status improved after the drug was stopped or the dose reduced, with complete resolution within 3 months [6].

Lipids are the other documented change. In the kidney transplant studies, hypercholesterolemia occurred in 43% to 46% and hypertriglyceridemia in 45% to 57% of rapamycin-treated patients, against 23% each on placebo [2]. In clinical trials of patients receiving Rapamune with or after cyclosporine, up to 90% needed lipid-lowering treatment, and up to 50% still had fasting cholesterol above 240 mg/dL [2]. Those are daily transplant doses, not weekly low doses.

A much smaller study shows how far lipids can move over weeks. Six kidney transplant patients on cyclosporine and prednisone, selected because they had previously had a hyperlipidemic response to sirolimus, were given 10 mg per day and continued as tolerated for 42 days. Mean total cholesterol rose from 214 to 322 mg/dL and mean triglycerides from 227 to 432 mg/dL, changes the authors described as repeatable, reversible and dose dependent [7].

What about immune suppression in the first month?

The Rapamune label carries a boxed warning that increased susceptibility to infection and the possible development of lymphoma and other malignancies may result from immunosuppression [2].

The immune-function result most often quoted in longevity discussions did not test sirolimus. Mannick and colleagues gave elderly volunteers RAD001 (everolimus), a different mTOR inhibitor, and found about a 20% better antibody response to influenza vaccination at relatively well-tolerated doses [8].

PEARL's reported outcomes were visceral adiposity, blood biomarkers, lean tissue and bone mineral content, and survey-based measures of health and well-being, with safety tracked through adverse events and blood monitoring [1]. The Kraig pilot ran for a median of at least 8 weeks in completers and had no longevity endpoint [3].

What the label says about monitoring

The label's monitoring is built for transplant patients. Sirolimus whole-blood trough concentrations are adjusted into a target range, with a trough obtained between days 5 and 7 after starting in high-immunologic-risk patients [2]. The label also states that any patient given Rapamune should be monitored for hyperlipidemia, with diet, exercise and lipid-lowering agents started as outlined by the National Cholesterol Education Program guidelines [2].

Thrombocytopenia and anemia are both in the label's 30%-or-more list for kidney transplant patients [2]. In hepatic impairment, sirolimus AUC rises 43% (mild), 94% (moderate) and 189% (severe), and the label reduces the maintenance dose by about one third in mild-to-moderate and about one half in severe impairment [2].

Interactions that shape the first month

• The Rapamune label identifies grapefruit juice as an inhibitor of sirolimus metabolism and states that it must not be taken with Rapamune or used to dilute it [2].
• The Rapamune label says to avoid concomitant use of strong CYP3A4/P-gp inducers such as rifampin and rifabutin and strong inhibitors such as ketoconazole, voriconazole, itraconazole, erythromycin, telithromycin and clarithromycin [2].
• The label also says to exercise caution with weaker modulators of CYP3A4 and P-gp [2]. Drugs it lists as able to increase sirolimus blood concentrations include bromocriptine, cimetidine, cisapride, clotrimazole, danazol, diltiazem, fluconazole, HIV and hepatitis C protease inhibitors, metoclopramide, nicardipine and verapamil. Drugs it lists as able to decrease them include carbamazepine, phenobarbital, phenytoin, rifapentine and St. John's wort [2]. Cannabidiol can raise sirolimus levels, and the label says therapeutic drug monitoring and dose reduction should be considered when the two are combined [2].
• The label says cyclosporine raises sirolimus concentrations, and that Rapamune should be taken 4 hours after cyclosporine [2].
• The label says sirolimus can cause fetal harm and recommends highly effective contraception during treatment and for 12 weeks after the last dose, started before therapy [2]. It found no clinically significant pharmacokinetic interaction with one specific oral contraceptive, norgestrel/ethinyl estradiol (Lo/Ovral), and does not address other contraceptive pills [2].

What the first month cannot show you

Human data on rapamycin and aging are short. In mice, rapamycin given from 600 days of age extended median and maximal lifespan, with a 14% increase for females and 9% for males based on age at 90% mortality [9]. An intermittent mouse regimen of 2 mg/kg every 5 days, started as late as 20 months of age, also extended lifespan in female C57BL/6J mice [10]. Mouse lifespan results do not describe a person's first month.

The PEARL authors concluded that low-dose intermittent rapamycin was relatively safe over 48 weeks in healthy, normative-aging adults and was associated with improvements in lean tissue mass and pain in women, and said future work will evaluate a broader range of doses [1]. Longevity use is off-label: the approved indications are kidney transplant rejection prophylaxis and LAM [2]. Compounded rapamycin, which the PEARL trial used, is not FDA-approved, and FDA does not verify the safety, effectiveness or quality of compounded drugs before they are marketed [4][1].

For product information, see the rapamycin page.