Everolimus

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Everolimus
Everolimus.svg
Everolimus ball-and-stick.png
Clinical data
PronunciationEverolimus /ˌɛvəˈroʊləməs/
Trade names Afinitor, Zortress
Other names42-O-(2-hydroxyethyl)rapamycin, RAD001
AHFS/Drugs.com Monograph
MedlinePlus a609032
License data
Pregnancy
category
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
Pharmacokinetic data
Elimination half-life ~30 hours [9]
Identifiers
  • 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
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.149.896 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C53H83NO14
Molar mass 958.240 g·mol−1
3D model (JSmol)
  • OCCO[C@@H]1CC[C@H](C[C@H]1OC)C[C@@H](C)[C@@H]4CC(=O)[C@H](C)/C=C(\C)[C@@H](O)[C@@H](OC)C(=O)[C@H](C)C[C@H](C)\C=C\C=C\C=C(/C)[C@@H](OC)C[C@@H]2CC[C@@H](C)[C@@](O)(O2)C(=O)C(=O)N3CCCC[C@H]3C(=O)O4
  • InChI=1S/C53H83NO14/c1-32-16-12-11-13-17-33(2)44(63-8)30-40-21-19-38(7)53(62,68-40)50(59)51(60)54-23-15-14-18-41(54)52(61)67-45(35(4)28-39-20-22-43(66-25-24-55)46(29-39)64-9)31-42(56)34(3)27-37(6)48(58)49(65-10)47(57)36(5)26-32/h11-13,16-17,27,32,34-36,38-41,43-46,48-49,55,58,62H,14-15,18-26,28-31H2,1-10H3/b13-11+,16-12+,33-17+,37-27+/t32-,34-,35-,36-,38-,39+,40+,41+,43-,44+,45+,46-,48-,49+,53-/m1/s1 Yes check.svgY
  • Key:HKVAMNSJSFKALM-GKUWKFKPSA-N Yes check.svgY
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Everolimus, sold under the brand name Afinitor among others, is a medication used as an immunosuppressant to prevent rejection of organ transplants [10] and as a targeted therapy in the treatment of renal cell cancer and other tumours. [11]

Contents

This compound also has a use in cardiovascular drug-eluting stent technologies to inhibit restenosis.[ medical citation needed ]

It is the 40-O-(2-hydroxyethyl) derivative of sirolimus and works similarly to sirolimus as an inhibitor of mammalian target of rapamycin (mTOR). [12]

It is marketed by Novartis under the trade names Zortress (US) and Certican (European Union and other countries) in transplantation medicine, and as Afinitor (general tumours) and Votubia (tumours as a result of Tuberous Sclerosis Complex (TSC)) in oncology.[ citation needed ]

It is on the World Health Organization's List of Essential Medicines. [13] It is available as a generic medication. [14]

Medical uses

Everolimus is approved for various conditions:

UK National Health Service

NHS England has been criticised for delays in deciding on a policy for the prescription of everolimus in the treatment of Tuberous Sclerosis. 20 doctors addressed a letter to the board in support of the charity Tuberous Sclerosis Association saying " around 32 patients with critical need, whose doctors believe everolimus treatment is their best or only option, have no hope of access to funding. Most have been waiting many months. Approximately half of these patients are at imminent risk of a catastrophic event (renal bleed or kidney failure) with a high risk of preventable death." [22] In May 2015 it was reported that Luke Henry and Stephanie Rudwick, the parents of a child suffering from Tuberous Sclerosis were trying to sell their home in Brighton to raise £30,000 to pay for treatment for their daughter Bethany who has tumours on her brain, kidneys and liver and suffers from up to 50 epileptic fits a day. [23]

Clinical trials

As of October 2010, Phase III trials are under way in gastric cancer, hepatocellular carcinoma, and lymphoma. [17] The experimental use of everolimus in refractory chronic graft-versus-host disease was reported in 2012. [24]

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. [25]

A study published in 2012, shows that everolimus sensitivity varies between patients depending on their tumor genomes. [26] A group of patients with advanced metastasic bladder carcinoma [27] treated with everolimus revealed a single patient who had a complete response to everolimus treatment for 26 months. The researchers sequenced the genome of this patient and compared it to different reference genomes and to other patients' genomes. They found that mutations in TSC1 led to a lengthened duration of response to everolimus and to an increase in the time to cancer recurrence. The mutated TSC1 apparently had made these tumors vulnerable to treatment with everolimus.[ medical citation needed ]

A phase IIa randomized, placebo-controlled everolimus clinical trial published in 2014 showed that everolimus improved the response to an influenza vaccine by 20% in healthy elderly volunteers. [28] A phase IIa randomized, placebo-controlled clinical trial published in 2018 showed that everolimus in combination with dactolisib decreased the rate of reported infections in an elderly population. [28]

Mechanism

Compared with the parent compound rapamycin, everolimus is more water-soluble. [29] Compared to rapamycin, everolimus is more selective for the mTORC1 protein complex, with little impact on the mTORC2 complex. [30] 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.[ medical citation needed ] Thus, everolimus has important effects on cell growth, cell proliferation and cell survival.

mTORC1 inhibition by everolimus has been shown to normalize tumor blood vessels, to increase tumor-infiltrating lymphocytes, and to improve adoptive cell transfer therapy. [31]

Additionally, mTORC2 is believed to play an important role in glucose metabolism and the immune system, suggesting that selective inhibition of mTORC1 by drugs such as everolimus could achieve many of the benefits of rapamycin without the associated glucose intolerance and immunosuppression. [30]

TSC1 and TSC2, the genes involved in tuberous sclerosis, 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. [32]

Everolimus binds to its protein receptor FKBP12, which directly interacts with mTORC1, inhibiting its downstream signaling. As a consequence, mRNAs that code for proteins implicated in the cell cycle and in the glycolysis process are impaired or altered, and tumor growth is inhibited. [32]

Adverse reactions

A trial using 10 mg/day in patients with NETs of GI or lung origin reported "Everolimus was discontinued for adverse reactions in 29% of patients and dose reduction or delay was required in 70% of everolimus-treated patients. Serious adverse reactions occurred in 42% of everolimus-treated patients and included 3 fatal events (cardiac failure, respiratory failure, and septic shock). The most common adverse reactions (incidence greater than or equal to 30%) were stomatitis, infections, diarrhea, peripheral edema, fatigue and rash. The most common blood abnormalities found (incidence greater than or equal to 50%) were anemia, hypercholesterolemia, lymphopenia, elevated aspartate transaminase (AST) and fasting hyperglycemia.". [20]

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. [33]

Role in liver transplantation

Although, sirolimus had generated fears over use of m-TOR inhibitors in liver transplantation recipients, due to possible early hepatic artery thrombosis and graft loss, use of everolimus in the setting of liver transplantation is promising. Jeng et al., [34] in their study of 43 patients, concluded the safety of everolimus in the early phase after living donor liver transplantation. In their study, no hepatic artery thrombosis or wound infection was noted. Also, a possible role of everolimus in reducing the recurrence of hepatocellular carcinoma after liver transplantation was correlated. A target trough level of 3 ng/mL at 3 months was shown to be beneficial in recipients with pre-transplant renal dysfunction. In their study, 6 of 9 renal failure patients showed significant recovery of renal function, whereas 3 showed further deterioration, one of whom required hemodialysis. [35] A positive impact on hepatocellular carcinoma (HCC) was observed when everolimus was used as primary immunosuppression starting as early as first week after living donor liver transplantation (LDLT) surgery. [36]

Use in vascular stents

Everolimus is used in drug-eluting coronary stents as an immunosuppressant to prevent restenosis. Abbott Vascular produce an everolimus-eluting stent (EES) called Xience Alpine. It utilizes the Multi-Link Vision cobalt chromium stent platform and Novartis' everolimus. The product is widely available globally including the US, the European Union, and Asia-Pacific (APAC) countries. Boston Scientific also market EESes, recent offerings being Promus Elite and Synergy.[ citation needed ]

Use in aging

Inhibition of mTOR, the molecular target of everolimus, extends the lifespan of model organisms including mice, [37] and mTOR inhibition has been suggested as an anti-aging therapy. Everolimus was used in a clinical trial by Novartis, and short-term treatment was shown to enhance the response to the influenza vaccine in the elderly, possible by reversing immunosenescence. [38] Everolimus treatment of mice results in reduced metabolic side effects compared to sirolimus. [30]

Related Research Articles

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Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide.

<span class="mw-page-title-main">Sirolimus</span> Pharmaceutical drug

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 tumor (PEComa). It has immunosuppressant functions in humans and is especially useful in preventing the rejection of kidney transplants. It is a mechanistic target of rapamycin (mTOR) kinase inhibitor that reduces the sensitivity of T cells and B cells to interleukin-2 (IL-2), inhibiting their activity.

<span class="mw-page-title-main">Tuberous sclerosis</span> Genetic condition causing non-cancerous tumours

Tuberous sclerosis complex (TSC) is a rare multisystem autosomal dominant genetic disease that causes non-cancerous tumours to grow in the brain and on other vital organs such as the kidneys, heart, liver, eyes, lungs and skin. A combination of symptoms may include seizures, intellectual disability, developmental delay, behavioral problems, skin abnormalities, lung disease, and kidney disease.

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References

  1. ↑ Use During Pregnancy and Breastfeeding
  2. ↑ "Prescription medicines: registration of new generic medicines and biosimilar medicines, 2017". Therapeutic Goods Administration (TGA). 21 June 2022. Retrieved 30 March 2024.
  3. ↑ "Summary of Product Characteristics (SmPC) - (emc)". Certican Tablets. 15 January 2021. Retrieved 30 December 2021.
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  5. ↑ "Afinitor- everolimus tablet Afinitor Disperz- everolimus tablet, for suspension". DailyMed. Retrieved 30 December 2021.
  6. ↑ "Zortress- everolimus tablet". DailyMed. Retrieved 30 December 2021.
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  8. ↑ "Votubia EPAR". European Medicines Agency. 17 September 2018. Retrieved 30 December 2021.
  9. ↑ Formica RN, Lorber KM, Friedman AL, Bia MJ, Lakkis F, Smith JD, Lorber MI (March 2004). "The evolving experience using everolimus in clinical transplantation". Transplantation Proceedings. 36 (2 Suppl): 495S–499S. doi:10.1016/j.transproceed.2004.01.015. PMID   15041395.
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  13. ↑ World Health Organization (2023). The selection and use of essential medicines 2023: web annex A: World Health Organization model list of essential medicines: 23rd list (2023). Geneva: World Health Organization. hdl: 10665/371090 . WHO/MHP/HPS/EML/2023.02.
  14. ↑ "First Generic Drug Approvals". U.S. Food and Drug Administration (FDA). 15 November 2021. Retrieved 30 December 2021.
  15. ↑ "Afinitor approved in US as first treatment for patients with advanced kidney cancer after failure of either sunitinib or sorafenib" (Press release). Novartis. 30 March 2009. Archived from the original on 3 April 2009. Retrieved 6 April 2009.
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  18. ↑ "FDA approves new treatment for rare type of pancreatic cancer". U.S. Food and Drug Administration (FDA). 6 May 2011. Archived from the original on 1 August 2014.
  19. ↑ "US FDA approves Novartis drug Afinitor for breast cancer". Reuters. 20 July 2012.
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  22. ↑ Lintern S (14 April 2015). "Policy delays risk 'preventable deaths', doctors warn NHS England". Health Service Journal. Retrieved 20 April 2015.
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  26. ↑ Iyer G, Hanrahan AJ, Milowsky MI, Al-Ahmadie H, Scott SN, Janakiraman M, Pirun M, Sander C, Socci ND, Ostrovnaya I, Viale A, Heguy A, Peng L, Chan TA, Bochner B, Bajorin DF, Berger MF, Taylor BS, Solit DB (October 2012). "Genome sequencing identifies a basis for everolimus sensitivity". Science. 338 (6104): 221. Bibcode:2012Sci...338..221I. doi:10.1126/science.1226344. PMC   3633467 . PMID   22923433.
  27. ↑ Clinical trial number NCT00805129 for "Everolimus (RAD001) in Metastatic Transitional Cell Carcinoma of the Urothelium" at ClinicalTrials.gov
  28. 1 2 Zhavoronkov A (2020). "Geroprotective and senoremediative strategies to reduce the comorbidity, infection rates, severity, and lethality in gerophilic and gerolavic infections". Aging . 12 (8): 6492–6510. doi:10.18632/aging.102988. PMC   7202545 . PMID   32229705.
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  30. 1 2 3 Arriola Apelo SI, Neuman JC, Baar EL, Syed FA, Cummings NE, Brar HK, Pumper CP, Kimple ME, Lamming DW (February 2016). "Alternative rapamycin treatment regimens mitigate the impact of rapamycin on glucose homeostasis and the immune system". Aging Cell. 15 (1): 28–38. doi:10.1111/acel.12405. PMC   4717280 . PMID   26463117.
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  32. 1 2 "AFINITOR (everolimus)". Novartis. Archived from the original on 8 March 2014. Retrieved 26 February 2014.
  33. ↑ Eisen HJ, Tuzcu EM, Dorent R, Kobashigawa J, Mancini D, Valantine-von Kaeppler HA, Starling RC, Sørensen K, Hummel M, Lind JM, Abeywickrama KH, Bernhardt P (August 2003). "Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients". The New England Journal of Medicine. 349 (9): 847–58. doi: 10.1056/NEJMoa022171 . PMID   12944570.
  34. ↑ Jeng LB, Thorat A, Hsieh YW, Yang HR, Yeh CC, Chen TH, Hsu SC, Hsu CH (April 2014). "Experience of using everolimus in the early stage of living donor liver transplantation". Transplantation Proceedings. 46 (3): 744–8. doi:10.1016/j.transproceed.2013.11.068. PMID   24767339.
  35. ↑ Jeng L, Thorat A, Yang H, Yeh CC, Chen TH, Hsu SC (2015). "Impact of Everolimus On the Hepatocellular Carcinoma Recurrence After Living Donor Liver Transplantation When Used in Early Stage: A Single Center Prospective Study". American Journal of Transplantation. 15 (suppl 3).
  36. ↑ Thorat A, Jeng LB, Yang HR, Yeh CC, Hsu SC, Chen TH, Poon KS (November 2017). "Assessing the role of everolimus in reducing hepatocellular carcinoma recurrence after living donor liver transplantation for patients within the UCSF criteria: re-inventing the role of mammalian target of rapamycin inhibitors". Annals of Hepato-Biliary-Pancreatic Surgery. 21 (4): 205–211. doi:10.14701/ahbps.2017.21.4.205. PMC   5736740 . PMID   29264583.
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