Everolimus is a derivative of Rapamycin (sirolimus), and works similarly to Rapamycin as an mTOR (mammalian target of rapamycin) inhibitor. It is currently used as an immunosuppressant to prevent rejection of organ transplants. In a similar fashion to other mTOR inhibitors Everolimus’ effect is solely on the mTORC1 protein and not on the mTORC2 protein.
|Brand mixtures||Not Available|
|Mass Spec||show(87.7 KB)|
|Superclass||Phenylpropanoids and Polyketides|
|Direct parent||Macrolide Lactams|
|Alternative parents||Alpha Amino Acid Esters; Macrolides and Analogues; Oxanes; Piperidines; Tertiary Carboxylic Acid Amides; Tertiary Amines; Secondary Alcohols; Carboxylic Acid Esters; Ketones; Hemiacetals; Carboxylic Acids; Polyamines; Primary Alcohols|
|Substituents||piperidine; oxane; tertiary carboxylic acid amide; carboxamide group; carboxylic acid ester; tertiary amine; ketone; hemiacetal; secondary alcohol; polyamine; primary alcohol; carboxylic acid; carboxylic acid derivative; ether; organonitrogen compound; amine; alcohol; carbonyl group|
|Classification description||This compound belongs to the macrolide lactams. These are cyclic polyketides containing both a cyclic amide and a cyclic ester group.|
|Indication||Everolimus is indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer (advanced HR+ BC) in combination with exemestane, after failure of treatment with letrozole or anastrozole. Indicated for the treatment of adult patients with progressive neuroendocrine tumors of pancreatic origin (PNET) with unresectable, locally advanced or metastatic disease. Indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of treatment with sunitinib or sorafenib. Indicated for the treatment of adult patients with renal angiomyolipoma and tuberous sclerosis complex (TSC), not requiring immediate surgery. Indicated in pediatric and adult patients with tuberous sclerosis complex (TSC) for the treatment of subependymal giant cell astrocytoma (SEGA) that requires therapeutic intervention but cannot be curatively resected.|
|Mechanism of action||Everolimus is a mTOR inhibitor that binds with high affinity to the FK506 binding protein-12 (FKBP-12), thereby forming a drug complex that inhibits the activation of mTOR. This inhibition reduces the activity of effectors downstream, which leads to a blockage in the progression of cells from G1 into S phase, and subsequently inducing cell growth arrest and apoptosis. Everolimus also inhibits the expression of hypoxia-inducible factor, leading to a decrease in the expression of vascular endothelial growth factor. The result of everolimus inhibition of mTOR is a reduction in cell proliferation, angiogenesis, and glucose uptake.|
|Absorption||In patients with advanced solid tumors, peak everolimus concentrations are reached 1 to 2 hours after administration of oral doses ranging from 5 mg to 70 mg. Following single doses, Cmax is dose-proportional between 5 mg and 10 mg. At doses of 20 mg and higher, the increase in Cmax is less than dose-proportional, however AUC shows dose-proportionality over the 5 mg to 70 mg dose range. Steady-state was achieved within 2 weeks following once-daily dosing. Dose Proportionality in Patients with SEGA (subependymal giant-cell astrocytomas) and TSC (tuberous sclerosis complex): In patients with SEGA and TSC, everolimus Cmin was approximately dose-proportional within the dose range from 1.35 mg/m2 to 14.4 mg/m2.|
|Volume of distribution|
The blood-to-plasma ratio of everolimus is 17% to 73%.
|Protein binding||~ 74% in both healthy patients and those with moderate hepatic impairment.|
Everolimus is a substrate of CYP3A4 and PgP (phosphoglycolate phosphatase). Three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus were the 6 primary metabolites detected in human blood. In vitro, everolimus competitively inhibited the metabolism of CYP3A4 and was a mixed inhibitor of the CYP2D6 substrate dextromethorphan.
|Route of elimination||After a single dose of radiolabeled everolimus was given to transplant patients receiving cyclosporine, the majority (80%) of radioactivity was recovered from the feces and only a minor amount (5%) was excreted in urine.|
|Half life||~30 hours.|
Following a 3 mg radiolabeled dose of everolimus, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine.
|Toxicity||IC50 of 0.63 nM.|
|SNP Mediated Effects||Not Available|
|SNP Mediated Adverse Drug Reactions||Not Available|
|Predicted ADMET features|
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|Experimental Properties||Not Available|
|AHFS Codes||Not Available|
|PDB Entries||Not Available|
|FDA label||show(548 KB)|
|Food Interactions||Not Available|
Pharmacological action: yes
|Serine/threonine-protein kinase mTOR||P42345||Details|
- Ettenger R, Hoyer PF, Grimm P, Webb N, Loirat C, Mahan JD, Mentser M, Niaudet P, Offner G, Vandamme-Lombaerts R, Hexham JM: Multicenter trial of everolimus in pediatric renal transplant recipients: results at three year. Pediatr Transplant. 2008 Jun;12(4):456-63. Pubmed
- Rostaing L, Kamar N: mTOR inhibitor/proliferation signal inhibitors: entering or leaving the field? J Nephrol. 2010 Mar-Apr;23(2):133-42. Pubmed
- George S, Bukowski RM: Role of everolimus in the treatment of renal cell carcinoma. Ther Clin Risk Manag. 2009 Oct;5(5):699-706. Epub 2009 Sep 15. Pubmed
- Teachey DT, Grupp SA, Brown VI: Mammalian target of rapamycin inhibitors and their potential role in therapy in leukaemia and other haematological malignancies. Br J Haematol. 2009 Jun;145(5):569-80. Epub 2009 Mar 16. Pubmed
- Albert S, Serova M, Dreyer C, Sablin MP, Faivre S, Raymond E: New inhibitors of the mammalian target of rapamycin signaling pathway for cancer. Expert Opin Investig Drugs. 2010 Jun 23. Pubmed
- Coppin C: Everolimus: the first approved product for patients with advanced renal cell cancer after sunitinib and/or sorafenib. Biologics. 2010 May 25;4:91-101. Pubmed
- Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed
Pharmacological action: unknown
|Cytochrome P450 3A4||P08684||Details|
- Preissner S, Kroll K, Dunkel M, Senger C, Goldsobel G, Kuzman D, Guenther S, Winnenburg R, Schroeder M, Preissner R: SuperCYP: a comprehensive database on Cytochrome P450 enzymes including a tool for analysis of CYP-drug interactions. Nucleic Acids Res. 2010 Jan;38(Database issue):D237-43. Epub 2009 Nov 24. Pubmed