Everolimus

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Everolimus
Everolimus.svg
Everolimus ball-and-stick.png
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[30.3.1.0 hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone
Clinical data
Licence data US FDA:link
Pregnancy cat.
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 CHEMBL1908360 N
Synonyms 42-O-(2-hydroxyethyl)rapamycin
Chemical data
Formula C53H83NO14 
Mol. mass 958.224 g/mol
 N (what is this?)  (verify)

Everolimus (INN) (earlier code name RAD001) is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an inhibitor of mammalian target of rapamycin (mTOR).

It is currently used as an immunosuppressant to prevent rejection of organ transplants and treatment of renal cell cancer and other tumours. Much research has also been conducted on everolimus and other mTOR inhibitors as targeted therapy 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. Everolimus also available with Biocon with the brand name of Evertor.

Approvals and indications[edit]

Everolimus is approved for various conditions:

Clinical trials[edit]

As of October 2010, Phase III trials are under way in gastric cancer, hepatocellular carcinoma and lymphoma.[7] The use of everolimus in refractory chronic graft-versus-host disease has been reported in 2012.[8]

Interim phase III trial results in 2011 showed that adding Afinitor (everolimus) to exemestane therapy against advanced breast cancer can significantly improve progression-free survival compared with exemestane therapy alone.[9] However, everolimus increases mortality in cancer patients.[10]

Furthermore, there is a study that shows that there is a different sensitivity to everolimus between patients depending on their genome.[11] Through a Phase II clinical trial done in patients that presented advanced metastasic bladder carcinoma (NCT00805129) [12] they found just one person that positively responded to everolimus treatment for 26 months. Thus, they decided to sequence the genome of this patient and to compare it to different reference genomes and to other patients' genomes. This way, they discovered that mutations in TSC1 lead to an increase in recurrence and to an increase in the response time to everolimus. Thus, it has been determined that everolimus is more efficient in those patients that present somatic mutations in TSC1.

Mechanism[edit]

In a similar fashion to other mTOR inhibitors its effect is solely on the mTORC1 protein complex and not on the mTORC2 complex. 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. Hence, everolimus plays an important role in cell growth, cell proliferation and cell survival. mTORC1 action is modulated by several mitogens, growth factors and nutrients.

TSC1 and TSC2 (which are the genes involved in tuberous sclerosis disease) act as tumor suppressor genes by regulating mTORC1 activity. Thus, either the loss or inactivation of one of these genes lead to the activation of mTORC1.[13]

Everolimus binds to its protein receptor FKBP12, which directly interacts with mTORC1 inhibiting its downstream signaling. As a consequence, mRNAs that codify proteins implicated in the cell cycle and in the glycolysis process are impared or altered, so tumor growth is inhibited. Hence, everolimus inhibits tumor cells' growth and proliferation.[13]

Role in heart transplantation[edit]

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.[14]

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

Use in vascular stents[edit]

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

See also[edit]

References[edit]

  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. doi:10.1016/j.transproceed.2004.01.015. 
  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. 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. Retrieved April 26, 2010. 
  4. ^ "Novartis’ Afinitor Cleared by FDA for Treating SEGA Tumors in Tuberous Sclerosis". 1 Nov 2010. 
  5. ^ http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm254350.htm
  6. ^ "US FDA approves Novartis drug Afinitor for breast cancer". Reuters. 20 Jul 2012. 
  7. ^ http://www.genengnews.com/gen-news-highlights/novartis-afinitor-cleared-by-fda-for-treating-sega-tumors-in-tuberous-sclerosis/81244159/
  8. ^ Lutz M, Kapp M, Grigoleit GU, Stuhler G, Einsele H, Mielke S (April 2012). "Salvage therapy with everolimus improves quality of life in patients with refractory chronic graft-versus-host disease". Bone Marrow Transplant 47 (S1): S410–S411. 
  9. ^ "Positive Trial Data Leads Novartis to Plan Breast Cancer Filing for Afinitor by Year End". 2011. 
  10. ^ Fatal AEs Higher with mTOR Drugs in Cancer. Med Page Today
  11. ^ [1]
  12. ^ [2]
  13. ^ a b [3]
  14. ^ 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. 

External links[edit]