Sirolimus, also known as rapamycin and sold under the brand name Rapamune among others, is a macrolide compound that is used to coat coronary stents, prevent organ transplant rejection, treat a rare lung disease called lymphangioleiomyomatosis, and treat perivascular epithelioid cell tumour (PEComa).[1][2][7] It has immunosuppressant functions in humans and is especially useful in preventing the rejection of kidney transplants. It is a mammalian target of rapamycin (mTOR) kinase inhibitor[2] that reduces the sensitivity of T cells and B cells to interleukin-2 (IL-2), inhibiting their activity.
This compound also has a use in cardiovascular drug-eluting stent technologies to inhibit restenosis.
It is produced by the bacterium Streptomyces hygroscopicus and was isolated for the first time in 1972, from samples of S. hygroscopicus found on Easter Island.[8][9][10] The compound was originally named rapamycin after the native name of the island, Rapa Nui.[7] Sirolimus was initially developed as an antifungal agent. However, this use was abandoned when it was discovered to have potent immunosuppressive and antiproliferative properties due to its ability to inhibit mTOR. It was approved by the US Food and Drug Administration (FDA) in 1999.[11] Hyftor (sirolimus gel) was authorized for topical treatment of facial angiofibroma in the European Union in May 2023.[12]
Medical uses
In the US, sirolimus, as Rapamune, is indicated for the prevention of organ transplant rejection[1] and for the treatment of lymphangioleiomyomatosis;[1] and, as Fyarro, in the form of protein-bound particles, for the treatment of adults with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumour (PEComa).[2]
In the EU, sirolimus, as Rapamune, is indicated for the prophylaxis of organ rejection in adults at low to moderate immunological risk receiving a renal transplant[4][13] and for the treatment of people with sporadic lymphangioleiomyomatosis with moderate lung disease or declining lung function;[4]
Adverse effects
The most common adverse reactions (≥30% occurrence, leading to a 5% treatment discontinuation rate) observed with sirolimus in clinical studies of organ rejection prophylaxis 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.[1]
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.[1]
The following adverse effects occurred in 3–20% of individuals taking sirolimus for organ rejection prophylaxis following a kidney transplant:[1]
Interactions
Sirolimus is metabolized by the CYP3A4 enzyme and is a substrate of the P-glycoprotein (P-gp) efflux pump; hence, inhibitors of either protein may increase sirolimus concentrations in blood plasma, whereas inducers of CYP3A4 and P-gp may decrease sirolimus concentrations in blood plasma.[1]
Pharmacology
Pharmacodynamics
Unlike the similarly named tacrolimus, 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 (mammalian Target Of Rapamycin, rapamycin being another name for sirolimus), and thereby blocks activation of T and B cells. Ciclosporin and tacrolimus inhibit the secretion of IL-2, by inhibiting calcineurin.[18]
The mode of action of sirolimus is to bind the cytosolic protein FK-binding protein 12 (FKBP12) like tacrolimus. Unlike the tacrolimus-FKBP12 complex, which inhibits calcineurin (PP2B), the sirolimus-FKBP12 complex inhibits the mTOR pathway by directly binding to mTOR Complex 1 (mTORC1).[18]
mTOR has also been called FRAP (FKBP-rapamycin-associated protein), RAFT (rapamycin and FKBP target), RAPT1, or SEP. The earlier names FRAP and RAFT were coined to reflect the fact that sirolimus must bind FKBP12 first, and only the FKBP12-sirolimus complex can bind mTOR.
Chemistry
Sirolimus is a natural product and macrocyclic lactone.[49]
Biosynthesis
The biosynthesis of the rapamycin core is accomplished by a type I polyketide synthase (PKS) in conjunction with a nonribosomal peptide synthetase (NRPS). The domains responsible for the biosynthesis of the linear polyketide of rapamycin are organized into three multienzymes, RapA, RapB, and RapC, which contain a total of 14 modules (figure 1). The three multienzymes are organized such that the first four modules of polyketide chain elongation are in RapA, the following six modules for continued elongation are in RapB, and the final four modules to complete the biosynthesis of the linear polyketide are in RapC.[50] Then, the linear polyketide is modified by the NRPS, RapP, which attaches L-pipecolate to the terminal end of the polyketide, and then cyclizes the molecule, yielding the unbound product, prerapamycin.[51]
Society and culture
Legal status
In February 2023, the Committee for Medicinal Products for Human Use of the European Medicines Agency adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Hyftor, intended for the treatment of angiofibroma. The applicant for this medicinal product is Plusultra pharma GmbH.[56] Hyftor was authorized for medical use in the European Union in May 2023.[57]
Sirolimus, as Rapamune solution, was approved for medical use in the United States in 1999;[11] and as Rapamune tablets in August 2000.[58]
Sirolimus, as Fyarro, was approved for medical use in the United States in November 2021.[59]
Research
Cancer
The antiproliferative effects of sirolimus may have a role in treating cancer. When dosed appropriately, sirolimus can enhance the immune response to tumor targeting[62] or otherwise promote tumor regression in clinical trials.[63] Sirolimus seems to lower the cancer risk in some transplant patients.[64]
Sirolimus was shown to inhibit the progression of dermal Kaposi's sarcoma in patients with renal transplants.[65] Other mTOR inhibitors, such as temsirolimus (CCI-779) or everolimus (RAD001), are being tested for use in cancers such as glioblastoma multiforme and mantle cell lymphoma. However, these drugs have a higher rate of fatal adverse events in cancer patients than control drugs.
Veterinary uses
A number of veterinary medicine teaching hospitals are participating in a long-term clinical study examining the effect of rapamycin on the longevity of dogs.[93]
A clinical trial led by NC State College of Veterinary Medicine (HALT), run at a number of veterinary hospitals across the US, found that rapamycin reverses the effects of hypertrophic cardiomyopathy in cats.[94]
In March 2025, the US Food and Drug Administration announced conditional approval of sirolimus delayed-release tablets (Felycin-CA1) for the management of ventricular hypertrophy in cats with subclinical hypertrophic cardiomyopathy.[95][96] This is the first product approved for use in cats with hypertrophic cardiomyopathy for any indication.[96]
See also
- List of drugs affected by grapefruit
Further reading
External links
- The Dirty Drug and the Ice Cream Tub Radiolab episode on the discovery of rapamycin
References
- Rapamune- sirolimus solution Rapamune- sirolimus tablet, sugar coated DailyMed, retrieved 26 November 2021^
- Fyarro- sirolimus injection, powder, lyophilized, for suspension DailyMed, retrieved 19 December 2021^
- Hyftor- sirolimus gel