Sirolimus, is also known as rapamycin.
It is sold under the brand name Rapamune.
It is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease lymphangioleiomyomatosis, and treat perivascular epithelioid cell tumor.
It especially useful in preventing the rejection of kidney transplants.
It is a mechanistic target of rapamycin kinase (mTOR) inhibitor that inhibits activation of T cells and B cells by reducing their sensitivity to interleukin-2 (IL-2).
Sirolimus has complex effects on the immune system: IL-12 goes up and IL-10 decreases, which suggests an immunostimulatory response, TNF and IL-6 are decreased, which suggests an immunosuppressive response.
Pregnancy category AU: C
Routes of administration by mouth, intravenous, topical
Bioavailability:
Oral solution, 18%, lower with high-fat meals; 18% tablet, higher with high-fat meals.
Protein binding 92%
Metabolism Liver
Elimination half-life 57–63 hours
Excretion Mostly fecal
It is produced by the bacterium Streptomyces hygroscopicus.
The compound was originally named rapamycin after the native name of the island, Rapa Nui.
Has potent immunosuppressive and antiproliferative properties due to its ability to inhibit mTOR.
Sirolimus is indicated for the prevention of organ transplant rejection and for the treatment of lymphangioleiomyomatosis .
Sirolimus is indicated for the treatment of adults with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumor.
The chief advantage sirolimus has over calcineurin inhibitors is its low toxicity toward kidneys.
Transplant patients maintained on calcineurin inhibitors long-term tend to develop impaired kidney function or even kidney failure; this can be avoided by using sirolimus instead.
It is particularly advantageous in patients with kidney transplants for hemolytic-uremic syndrome, as this disease is likely to recur in the transplanted kidney if a calcineurin-inhibitor is used.
Sirolimus can also be used alone, or in conjunction with a calcineurin inhibitor (such as tacrolimus), and/or mycophenolate mofetil, to provide steroid-free immunosuppression regimens.
Impaired wound healing and thrombocytopenia are possible side effects of sirolimus;.
It is approved rapamycin to treat lymphangioleiomyomatosis (LAM), a rare, progressive lung disease that primarily affects women of childbearing age.
LAM involves lung tissue infiltration with smooth muscle-like cells with mutations of the tuberous sclerosis complex gene (TSC2).
Loss of TSC2 gene function activates the mTOR signaling pathway, resulting in the release of lymphangiogenic growth factors, and Sirolimus blocks this pathway.
Side effects: mouth and lip ulcers, diarrhea, abdominal pain, nausea, sore throat, acne, chest pain, leg swelling, upper respiratory tract infection, headache, dizziness, muscle pain and elevated cholesterol.
Serious side effects including hypersensitivity and swelling have been observed in renal transplant patients.
The antiproliferative effect of sirolimus has also been used in conjunction with coronary stents to prevent restenosis in coronary arteries following balloon angioplasty.
The sirolimus in a polymer coating has a controlled release through the healing period following coronary intervention.
Studies have demonstrated lower restenosis rates in patients treated with sirolimus-eluting stents when compared to bare-metal stents, resulting in fewer repeat procedures.
Sirolimus is used to treat vascular malformations, decreaing pain and the fullness of vascular malformations, improve coagulation levels, and slow the growth of abnormal lymphatic vessels.
Sirolimus is a treatment option for both vascular tumors and vascular malformations, as a mammalian target of rapamycin (mTOR), capable of integrating signals from the PI3K/AKT pathway to coordinate proper cell growth and proliferation.
It is a treatment for proliferative vascular tumors through the control of tissue overgrowth disorders caused by inappropriate activation of the PI3K/AKT/mTOR pathway.
Sirolimus is a topical treatment of angiofibromas with tuberous sclerosis complex: facial angiofibromas occur in 80% of patients with TSC.
Topical sirolimus treatment of facial angiofibromas found improvement was observed in 94%.
The most common adverse reactions (≥30% occurrence, leading to a 5% treatment discontinuation rate) observed with sirolimus in individuals with kidney transplants include: peripheral edema, hypercholesterolemia, abdominal pain, headache, nausea, diarrhea, pain, constipation, hypertriglyceridemia, hypertension, increased creatinine, fever, urinary tract infection, anemia, arthralgia, and thrombocytopenia.
The most common adverse reactions (≥20% occurrence, leading to an 11% treatment discontinuation rate) observed with sirolimus in clinical studies for the treatment of lymphangioleiomyomatosis are: peripheral edema, hypercholesterolemia, abdominal pain, headache, nausea, diarrhea, chest pain, stomatitis, nasopharyngitis, acne, upper respiratory tract infection, dizziness, and myalgia.
The following adverse effects occurred in 3–20% of individuals taking sirolimus for organ rejection prophylaxis following a kidney transplant.
System Adverse effects:
Sepsis, lymphocele, herpes zoster infection, herpes simplex infection
Cardiovascular: Venous thromboembolism, rapid heart rate
Digestive Stomatitis
Hematologic/lymphatic Thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS), leukopenia
Metabolic Abnormal healing, increased lactic dehydrogenase (LDH), hypokalemia, diabetes
Musculoskeletal Bone necrosis
Respiratory Pneumonia, epistaxis
Skin Melanoma, squamous cell carcinoma, basal cell carcinoma
Urogenital Pyelonephritis, ovarian cysts, menstrual disorders (amenorrhea and menorrhagia)
Diabetes-like symptoms
While sirolimus inhibition of mTORC1 appears to mediate the drug’s benefits, it also inhibits mTORC2, which results in diabetes-like symptoms, may additionally increase the risk of type 2 diabetes.
Lung toxicity is a complication associated with sirolimus therapy, in the form of interstitial pneumonitis.
The interstitial pneumonitis is more common in patients with underlying lung disease.
Sirolimus use in transplants may increase mortality due to an increased risk of infections.
It may increase an individual’s risk for contracting skin cancers from exposure to sunlight or UV radiation.
It is associated with a risk of developing lymphoma.
Sirolimus use is associated with an increased risk of experiencing impaired or delayed wound healing, particularly if they have a body mass index in excess of 30 kg/m2.
Sirolimus is metabolized by the CYP3A4 enzyme and is a substrate of the P-glycoprotein efflux pump; inhibitors of either protein may increase sirolimus concentrations, and inducers of CYP3A4 and P-gp may decrease sirolimus concentrations in blood plasma.
Sirolimus is not a calcineurin inhibitor, but it has a similar suppressive effect on the immune system.
Sirolimus inhibits IL-2 and other cytokine receptor-dependent signal transduction mechanisms, via action on mTOR, and thereby blocks activation of T and B cells.
Sirolimus directly binding to mTOR Complex 1 (mTORC1).
Sirolimus has an elimination half-life of 57–63 hours.
The absorption of sirolimus into the blood stream from the intestine varies widely between patients: up to eight times more exposure than others for the same dose.
Drug levels are required to monitor the dose.
Sirolimus is a natural product and macrocyclic lactone.
Srolimus can enhance the immune response to tumor targeting or otherwise promote tumor regression.
Sirolimus seems to lower the cancer risk in some transplant patients.
Sirolimus was shown to inhibit the progression of dermal Kaposi’s sarcoma in patients with renal transplants.
Other mTOR inhibitors include temsirolimus, and everolimus.
Sirolimus is used treating tuberous sclerosis complex (TSC), a congenital disorder that predisposes those afflicted to benign tumor growth in the brain, heart, kidneys, skin, and other organs.
Sirolimus has potential for use as a longevity-promoting drug, with evidence pointing to its ability to prevent age-associated decline of cognitive and physical health.
When applied topically, rapamycin can regenerate collagen and reverse clinical signs of aging in elderly patients.
Oxidized LDL cholesterol is a major contributor to atherosclerosis, and
Rapamycin can accelerate degradation of oxidized LDL cholesterol in endothelial cells, thereby lowering the risk.
Sudies in cells, animals, and humans have suggested that mTOR activation as process underlying systemic lupus erythematosus and that inhibiting mTOR with rapamycin may be a disease-modifying treatment.
Sirolimus has shown evidence of being helpful in alleviating symptoms and reducing the size lymphatic malformation.
Rapamycin can mitigate GVHD by increasing the proliferation of regulatory T cells, inhibiting cytotoxic T cells and lowering the differentiation of effector T cells.