Sirolimus

Generic Name
Sirolimus
Brand Names
Fyarro, Hyftor, Rapamune
Drug Type
Small Molecule
Chemical Formula
C51H79NO13
CAS Number
53123-88-9
Unique Ingredient Identifier
W36ZG6FT64
Background

Sirolimus, also known as rapamycin, is a macrocyclic lactone antibiotic produced by bacteria Streptomyces hygroscopicus, which was isolated from the soil of the Vai Atari region of Rapa Nui (Easter Island). It was first isolated and identified as an antifungal agent with potent anticandida activity; however, after its potent antitumor and immunosuppressive activities were later discovered, it was extensively investigated as an immunosuppressive and antitumour agent. Its primary mechanism of action is the inhibition of the mammalian target of rapamycin (mTOR), which is a serine/threonine-specific protein kinase that regulates cell growth, proliferation, and survival. mTOR is an important therapeutic target for various diseases, as it was shown to regulate longevity and maintain normal glucose homeostasis. Targeting mTOR received more attention especially in cancer, as mTOR signalling pathways are constitutively activated in many types of human cancer.

Sirolimus was first approved by the FDA in 1999 for the prophylaxis of organ rejection in patients aged 13 years and older receiving renal transplants. In November 2000, the drug was recognized by the European Agency as an alternative to calcineurin antagonists for maintenance therapy with corticosteroids. In May 2015, the FDA approved sirolimus for the treatment of patients with lymphangioleiomyomatosis. In November 2021, albumin-bound sirolimus for intravenous injection was approved by the FDA for the treatment of adults with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumour (PEComa). Sirolimus was also investigated in other cancers such as skin cancer, Kaposi’s Sarcoma, cutaneous T-cell lymphomas, and tuberous sclerosis. The topical formulation of sirolimus, marketed as HYFTOR, was approved by the FDA in April 2022: this marks the first topical treatment approved in the US for facial angiofibroma associated with tuberous sclerosis complex.

Indication

Sirolimus is indicated for the prophylaxis of organ rejection in patients aged 13 years or older receiving renal transplants. In patients at low-to moderate-immunologic risk, it is recommended that sirolimus be used initially in a regimen with cyclosporine and corticosteroids; cyclosporine should be withdrawn two to four months after transplantation. In patients at high-immunologic risk (defined as Black recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high panel-reactive antibodies [PRA; peak PRA level > 80%]), it is recommended that sirolimus be used in combination with cyclosporine and corticosteroids for the first year following transplantation.

It is also used to treat lymphangioleiomyomatosis.

In the US, albumin-bound sirolimus for intravenous injection is indicated for the treatment of adult patients with locally advanced unresectable or metastatic malignant perivascular epithelioid cell tumour (PEComa).

In Europe, it is recommended that sirolimus for the prophylaxis of organ rejection in renal transplants is used in combination with cyclosporin microemulsion and corticosteroids for two to three months. Sirolimus may be continued as maintenance therapy with corticosteroids only if cyclosporin microemulsion can be progressively discontinued.

Topical sirolimus is indicated for the treatment of facial angiofibroma associated with tuberous sclerosis in adults and pediatric patients six years of age and older.

Associated Conditions
Chordomas, Facial Angiofibroma, Graft-versus-host Disease (GVHD), Heart Transplant Rejection, Liver Transplant Rejection, Lung Transplant Rejection, Lymphangioleiomyomatosis (LAM), Renal Angiomyolipomas, Transplanted Organ Rejection, Metastatic malignant Perivascular Epithelioid Cell Neoplasms, Unresectable, locally advanced malignant Perivascular Epithelioid Cell Neoplasms
Associated Therapies
-

Phase 1 Study With Sorafenib and Sirolimus

First Posted Date
2007-07-31
Last Posted Date
2009-09-18
Lead Sponsor
Radboud University Medical Center
Registration Number
NCT00509613
Locations
🇳🇱

UMC St Radboud, Nijmegen, Netherlands

Study Evaluating the Efficacy and Safety of Cyclosporine Reduction in Kidney Transplant Recipients Receiving Sirolimus

Phase 4
Completed
Conditions
First Posted Date
2007-07-27
Last Posted Date
2007-07-27
Lead Sponsor
Wyeth is now a wholly owned subsidiary of Pfizer
Target Recruit Count
385
Registration Number
NCT00507793

Thymoglobulin, Sirolimus and Mycophenolate Mofetil for Prevention of Acute Graft-Versus-Host Disease (GVHD)

First Posted Date
2007-07-25
Last Posted Date
2020-09-24
Lead Sponsor
M.D. Anderson Cancer Center
Target Recruit Count
13
Registration Number
NCT00506948
Locations
🇺🇸

UT MD Anderson Cancer Center, Houston, Texas, United States

Sirolimus in Treating Patients With Advanced Pancreatic Cancer

Phase 2
Completed
Conditions
Interventions
First Posted Date
2007-07-11
Last Posted Date
2016-10-19
Lead Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Target Recruit Count
47
Registration Number
NCT00499486
Locations
🇺🇸

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland, United States

Fibrosis in Renal Allografts

First Posted Date
2007-06-28
Last Posted Date
2008-11-26
Lead Sponsor
University Hospital, Antwerp
Target Recruit Count
100
Registration Number
NCT00493194
Locations
🇧🇪

University Hospital Gent, Gent, Oost-Vlaanderen, Belgium

🇧🇪

University Hospital Brussels, Brussels (Jette), Brabant, Belgium

🇧🇪

University Hospital Antwerp, Edegem, Antwerp, Belgium

Sirolimus Treatment in Patients With Autosomal Dominant Polycystic Kidney Disease: Renal Efficacy and Safety

Phase 2
Completed
Conditions
Interventions
First Posted Date
2007-06-26
Last Posted Date
2013-04-24
Lead Sponsor
Mario Negri Institute for Pharmacological Research
Target Recruit Count
22
Registration Number
NCT00491517
Locations
🇮🇹

Hospital "Azienda Ospedaliera Ospedali Riuniti di Bergamo" Unit of Neprology and Dialysis, Bergamo, Italy

Trial of Efficacy and Safety of Sirolimus in Tuberous Sclerosis and LAM

First Posted Date
2007-06-25
Last Posted Date
2008-04-30
Lead Sponsor
Cardiff University
Target Recruit Count
14
Registration Number
NCT00490789
Locations
🇬🇧

Royal Sussex County Hospital, Brighton, United Kingdom

🇬🇧

City Hospital, Nottingham, United Kingdom

🇬🇧

University Hospital of Wales, Cardiff, Wales, United Kingdom

Study Investigating Rapamune For Post-Marketing Surveillance

Completed
Conditions
Interventions
First Posted Date
2007-06-08
Last Posted Date
2017-01-16
Lead Sponsor
Pfizer
Target Recruit Count
209
Registration Number
NCT00484094
Locations
🇰🇷

Gangnam Severance Hospital, Yonsei University Health System, Seoul, Korea, Republic of

🇰🇷

Samsung Medical Center, Seoul, Korea, Republic of

🇰🇷

Yeungnam University Medical Center, Daegu, Korea, Republic of

and more 8 locations
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