Everolimus

Everolimus
Systematic (IUPAC) name
dihydroxy-12-[(2R)-1-[(1S,3R,4R)-4-(2-hydroxyethoxy)-3-methoxycyclohexyl]propan-2-yl]-19,30-dimethoxy-15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo[30.3.1.04,9]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone
Clinical data
Licence data US FDA:link
Pregnancy cat. D(US)
Legal status Prescription only
Routes Oral
Pharmacokinetic data
Half-life ~30 hours[1]
Identifiers
CAS number 159351-69-6 YesY
ATC code L01XE10 L04AA18
PubChem CID 6442177
DrugBank DB01590
ChemSpider 21106307 YesY
UNII 9HW64Q8G6G YesY
KEGG D02714 YesY
ChEMBL CHEMBL1201755 N
Synonyms 42-O-(2-hydroxyethyl)rapamycin
Chemical data
Formula C53H83NO14 
Mol. mass 958.224 g/mol
SMILES eMolecules & PubChem
 N(what is this?)  (verify)

Everolimus (RAD-001) is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an mTOR (mammalian target of rapamycin) inhibitor.

It is currently used as an immunosuppressant to prevent rejection of organ transplants and treatment of renal cell cancer. Much research has also been conducted on everolimus and other mTOR inhibitors for use in a number of cancers.

It is marketed by Novartis under the tradenames Zortress (USA) and Certican (Europe and other countries) in transplantation medicine, and Afinitor in oncology.

Contents

Approvals and indications

Everolimus is approved for various conditions:

  • Advanced kidney cancer (approved in March 2009)[2]
  • Prevention of organ rejection after renal transplant(April 2010)[3]
  • Subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis (TS) in patients who are not suitable for surgical intervention (October 2010)[4]
  • Progressive or metastatic pancreatic neuroendocrine tumors not surgically removable (May 2011)[5]

Clinical trials

As of October 2010, Phase III trials are under way in breast cancer, gastric cancer, hepatocellular carcinoma and lymphoma.[6]

Interim phase III trial results in 2011 show that adding Afinitor (everolimus) to exemestane therapy against advanced breast cancer can significantly improve progression-free survival compared with exemestane therapy alone.[7]

Mechanism

In a similar fashion to other mTOR inhibitors its effect is solely on the mTORC1 protein and not on the mTORC2 protein. This can lead to a hyper-activation of the kinase AKT via inhibition on the mTORC1 negative feedback loop while not inhibiting the mTORC2 positive feedback to AKT. This AKT elevation can lead to longer survival in some cell types.

Role in heart transplantation

Everolimus may have a role in heart transplantation as it has been shown to reduce chronic allograft vasculopathy in such transplants. It also may have a similar role to sirolimus in kidney and other transplants.[8]

Because hypercholesterolemia and hypertriglyceridemia have been reported, monitoring of blood lipid level is recommended.

Use in vascular stents

Everolimus is used in drug-eluting coronary stents as an immunosuppressant to prevent restenosis. Abbott Vascular produces an everolimus-eluting stent called the Xience V. It utilizes the Multi-Link Vision cobalt chromium stent platform and Novartis' everolimus. The product is also currently an investigational device in the United States and Japan. It is also available under a private-label version called the PROMUS Everolimus-Eluting Coronary Stent System and it is currently available in most major European and Asia-Pacific markets.

References

  1. ^ R.N Formica Jra, K.M Lorberb, A.L Friedmanb, M.J Biaa, F Lakkisa, J.D Smitha, M.I Lorber (March 2004). "The evolving experience using everolimus in clinical transplantation". Elsevier 36 (2): S495–S499. http://www.transplantation-proceedings.org/article/S0041-1345(04)00016-8/abstract. 
  2. ^ "Afinitor approved in US as first treatment for patients with advanced kidney cancer after failure of either sunitinib or sorafenib" (Press release). Novartis. 2009-03-30. http://www.novartis.com/newsroom/media-releases/en/2009/1301801.shtml. Retrieved April 6, 2009. 
  3. ^ "Novartis receives US FDA approval for Zortress (everolimus) to prevent organ rejection in adult kidney transplant recipients" (Press release). Novartis. 2010-04-22. http://www.novartis.com/newsroom/media-releases/en/2010/1406625.shtml. Retrieved April 26, 2010. 
  4. ^ "Novartis’ Afinitor Cleared by FDA for Treating SEGA Tumors in Tuberous Sclerosis". 1 Nov 2010. http://www.genengnews.com/gen-news-highlights/novartis-afinitor-cleared-by-fda-for-treating-sega-tumors-in-tuberous-sclerosis/81244159/. 
  5. ^ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm254350.htm
  6. ^ http://www.genengnews.com/gen-news-highlights/novartis-afinitor-cleared-by-fda-for-treating-sega-tumors-in-tuberous-sclerosis/81244159/
  7. ^ "Positive Trial Data Leads Novartis to Plan Breast Cancer Filing for Afinitor by Year End". 2011. http://www.genengnews.com/gen-news-highlights/positive-trial-data-leads-novartis-to-plan-breast-cancer-filing-for-afinitor-by-year-end/81245384/. 
  8. ^ Eisen HJ, Tuzcu EM, Dorent R, et al. (August 2003). "Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients". N. Engl. J. Med. 349 (9): 847–58. doi:10.1056/NEJMoa022171. PMID 12944570. http://content.nejm.org/cgi/pmidlookup?view=short&pmid=12944570&promo=ONFLNS19. 

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Look at other dictionaries:

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  • Everolimus — Strukturformel Allgemeines Freiname Everolimus Andere Namen …   Deutsch Wikipedia

  • everolimus — noun A derivative of rapamycin, used as an immunosuppressant to prevent rejection of organ transplants …   Wiktionary

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