Everolimus

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Structural formula
Structural formula of everolimus
General
Non-proprietary name Everolimus
other names
  • RAD-001
  • IUPAC : Dihydroxy-12 - [(2 R ) -1 - [(1 S , 3 R , 4 R ) -4- (2-hydroxyethoxy) -3-methoxycyclohexyl] propan-2-yl] -19,30-dimethoxy -15,17,21,23,29,35-hexamethyl-11,36-dioxa-4-azatricyclo [3/30/1/04,9] hexatriaconta-16,24,26,28-tetraene-2,3,10,14 , 20-penton
Molecular formula C 53 H 83 NO 14
External identifiers / databases
CAS number 159351-69-6
EC number 621-003-9
ECHA InfoCard 100.149.896
PubChem 6442177
ChemSpider 21106307
DrugBank DB01590
Wikidata Q421052
Drug information
ATC code
Drug class
properties
Molar mass 958.224 g mol −1
safety instructions
Please note the exemption from the labeling requirement for drugs, medical devices, cosmetics, food and animal feed
GHS labeling of hazardous substances
08 - Dangerous to health

danger

H and P phrases H: 372-412
P: 273-314
As far as possible and customary, SI units are used. Unless otherwise noted, the data given apply to standard conditions .

Everolimus ( RAD-001 ) is an immunosuppressant with macrolide (macrocyclic lactone) and belongs to the class of drugs of mTOR - inhibitors . It is used by Novartis in transplantation medicine under the name Certican ® ( Europe ) and Zortress ® ( USA ) and in the oncology under the name Afinitor ® marketed.

Mechanism of action

Everolimus is a derivative of the sirolimus (rapamycin) isolated from the streptomycete Streptomyces hygroscopicus and has the same mechanism of action: through the formation of a complex with the protein mTOR (“mammalian target of rapamycin”, German about “target of rapamycin in mammals”), a 282  kDa major serine / threonine - protein kinase is inactivated this. mTOR is part of the two protein complexes mTORC1 and mTORC2 , which use various signal transduction pathways to promote the transcription and translation of various proteins and thus the proliferation of T lymphocytes in particular . By inhibiting mTOR , both the activation and the progression of the T cells from the G1 phase to the S phase of the cell cycle are prevented.

Side effects

The most important side effects of everolimus are infections , which are mainly caused by myelosuppression with consequent leukopenia . Anemia and thrombocytopenia are also in the foreground. Other common undesirable effects are wound healing disorders , pneumonitis , pleural and pericardial effusions and increased liver enzyme levels .

application areas

Everolimus was originally developed for the indication of prophylactic immunosuppression after a kidney or heart transplant. For this purpose, approval was granted in the European Union in 2003 in combination with reduced doses of cyclosporine . After another study, it was also approved for use in kidney transplants in the USA in 2009. In combination with low-dose calcineurin inhibitors (cyclosporine, tacrolimus ), the substance shows synergistic effects of immunosuppression. In addition, the use of everolimus after organ transplantation results in significantly lower rates of infection with the cytomegalovirus . However, wound healing may be delayed, especially in patients with a BMI over 32. Everolimus is marketed under the brand name Zortress in the US and Certican in the EU and other parts of the world.

Everolimus has also been approved in combination with tacrolimus to prevent rejection reactions in liver transplants since October 31, 2012. Everolimus is also approved for second-line therapy in metastatic renal cell carcinoma , as well as for the treatment of subependymal giant cell astrocytoma associated with tuberous sclerosis and for the treatment of advanced or metastatic neuroendocrine pancreatic tumors .

Furthermore, clinical studies on the use in patients with breast cancer , stomach cancer , liver cell cancer and malignant lymphoma were carried out. In addition, the use of everolimus in a refractory chronic graft-versus-host reaction has been reported.

Web links

Individual evidence

  1. a b Everolimus data sheet from Sigma-Aldrich , accessed on October 28, 2016 ( PDF ).
  2. ^ Voss MH, Molina AM, Motzer RJ: mTOR inhibitors in advanced renal cell carcinoma. In: Hematol Oncol Clin North Am 25, 2011, pp. 835-852.
  3. Nashan B. and F. Citterio Wound Healing: Complications and the use of mammalian target of rapamycin inhibitor in Kidney Transplantation: A Critical review of the literature . In: Transplantation 2012 Aug 30; PMID 22941182
  4. Vitko Š. et al . Everolimus (Certican) 12-month safety and efficacy versus mycophenolate mofetil in de novo renal transplant recipients . Transplant 2004; 78: 1532.73. PMID 15599319
  5. Vitko Š. et al : Three-year efficacy and safety results from a study of everolimus versus mycophenolate mofetil in de novo renal transplant patients. Am J Transplant 2005; 5: 2521; PMID 16162203
  6. Lorber MI. et al . Everolimus versus mycophenolate mofetil in the prevention of rejection in de novo renal transplant recipients: a 3-year randomized, multicenter, phase III study . Transplant 2005; 80: 244; PMID 16041270
  7. ^ Eisen HJ et al . Everolimus for the prevention of allograft rejection and vasculopathy in cardiac-transplant recipients . N Engl J Med 2003; 349: 847; PMID 12944570
  8. Nashan B, Curtis J, Ponticelli C, et al . Everolimus and reduced-exposure cyclosporine in de novo renal-transplant recipients: a three-year phase II, randomized, multicenter, open-label study . Transplant 2004; 78: 1332; PMID 15548972
  9. Nashan B. The role of Certican (everolimus, rad) in the many pathways of chronic rejection . Transplant Proc 2001; 33: 3215 .; PMID 11750380
  10. New drugs in pipeline 2003 Everolimus (Certican®): Immunosuppression in transplants ( Memento of the original from June 18, 2014 in the Internet Archive ) Info: The archive link has been inserted automatically and has not yet been checked. Please check the original and archive link according to the instructions and then remove this notice. @1@ 2Template: Webachiv / IABot / www.medknowledge.de
  11. Tedesco Silva H Jr et al . Everolimus plus reduced- exposure CsA versus mycophenolic acid plus standard-exposure CsA in renal-transplant recipients . On J Transplant 2010; 10: 1401; PMID 20455882
  12. dailymed: WARNING: IMMUNOSUPPRESSION AND RENAL FUNCTION , April 2010.
  13. Campistol JM. et al. Everolimus and long-term outcomes in renal transplantation . Transplantation. 2011 Aug 15; 92 (3 Suppl): S3-26; PMID 21799392
  14. Nashan B. et al. : Review of Cytomegalovirus Infection Findings With Mammalian Target of Rapamycin Inhibitor-Based Immunosuppressive Therapy in De Novo Renal Transplant Recipients . Transplantation 2012; 93: 1075-1085; PMID 22683823
  15. Nashan B. and F. Citterio Wound Healing: Complications and the use of mammalian target of rapamycin inhibitor in Kidney Transplantation: A Critical review of the literature . Transplant 2012 Aug 30; PMID 22941182
  16. journalMED: Approval for everolimus in liver transplantation from November 8, 2012.
  17. Fischer L. et al. : A randomized, controlled study to assess the conversion from calcineurin inhibitors to everolimus after liver transplantation - PROTECT. Am J Transplant. 2012; 12 (7): 1855-1865 PMID 22494671
  18. De Simone P. et al. : Everolimus With Reduced Tacrolimus Improves Renal Function in De Novo Liver Transplant Recipients: A Randomized Controlled Trial . Am J Transplant. 2012 Aug 6. doi : 10.1111 / j.1600-6143.2012.04212.x . PMID 22882750
  19. Battelli C, Cho DC: mTOR inhibitors in renal cell carcinoma. In: Therapy 8, 2011, pp. 359-367.
  20. Turner SG, Peters KB, Vredenburgh JJ, Desjardins A, Friedman HS, Reardon DA: Everolimus tablets for patients with subependymal giant cell astrocytoma. In: Expert Opin Pharmacother . 12, 2011, pp. 2265-2269.
  21. Kulke MH, Bendell J, Kvols L, Picus J, Pommier R, Yao J: Evolving diagnostic and treatment strategies for pancreatic neuroendocrine tumors. In: J Hematol Oncol 4, 2011, pp. 1-8.
  22. Morrow PK, Wulf GM, Ensor J, Booser DJ, Moore JA, Flores PR, Xiong Y, Zhang S, Krop IE, Winer EP, Kindelberger DW, Coviello J, Sahin AA, Nuñez R, Hortobagyi GN, Yu D, Esteva FJ: Phase I / II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy. In: J Clin Oncol 29, 2011, pp. 3126-3132.
  23. Novartis reports data at EBCC-9 for secondary survival endpoint of Afinitor trial in HR + / HER2- advanced breast cancer ( Memento from April 24, 2015 in the Internet Archive ), PM Novartis from March 19, 2014, accessed on March 20, 2014
  24. Lim T, Lee J, Lee DJ, Lee HY, Han B, Baek KK, Ahn HK, Lee SJ, Park SH, Park JO, Park YS, Lim HY, Kim KM, Kang WK: Phase I trial of capecitabine plus everolimus (RAD001) in patients with previously treated metastatic gastric cancer. In: Cancer Chemother Pharmacol . 68, 2011, pp. 255-262.
  25. Zhu AX, Abrams TA, Miksad R, Blaszkowsky LS, Meyerhardt JA, Zheng H, Muzikansky A, Clark JW, Kwak EL, Schrag D, Jors KR, Fuchs CS, Iafrate AJ, Borger DR, Ryan DP: Phase 1/2 study of everolimus in advanced hepatocellular carcinoma. In: Cancer [Epub ahead of print] , 2011.
  26. Argyriou P Economopoulou P Papageorgiou S: The Role of mTOR inhibitor for the treatment of B-cell lymphomas. In: Adv Hematol 435342, 2012, pp. 1-13.
  27. Witzig TE, Reeder CB, LaPlant BR, Gupta M, Johnston PB, Micallef IN, Porrata LF, Ansell SM, Colgan JP, Jacobsen ED, Ghobrial IM, Habermann TM: A phase II trial of the oral mTOR inhibitor everolimus in relapsed aggressive lymphoma. In: Leukemia 25, 2011, pp. 341-347.
  28. Mielke S , Lutz M, Schmidhuber J, Kapp M, Ditz D, Ammer J, Einsele H , Grigoleit GU, Holler E, Wolff D: Salvage therapy with everolimus reduces the severity of treatment-refractory chronic GVHD without impairing disease control: A. dual center retrospective analysis. In: Bone Marrow Transplant 49 (11), November 2014, pp. 1412-1418. doi : 10.1038 / bmt.2014.170 PMID 25089598 .