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Identification
NameEverolimus
Accession NumberDB01590
TypeSmall Molecule
GroupsApproved
Description

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.

Structure
Thumb
Synonyms
SynonymLanguageCode
AfinitorNot AvailableNot Available
CerticanNot AvailableNot Available
RAD001Not AvailableNot Available
SDZ-RADNot AvailableNot Available
VOTUBIANot AvailableNot Available
ZortressNot AvailableNot Available
SaltsNot Available
Brand names
NameCompany
AfinitorNovartis
CerticanNovartis
VOTUBIANovartis
ZortressNovartis
Brand mixturesNot Available
Categories
CAS number159351-69-6
WeightAverage: 958.2244
Monoisotopic: 957.581356369
Chemical FormulaC53H83NO14
InChI KeyHKVAMNSJSFKALM-CYUZEOOHSA-N
InChI
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-/m0/s1
IUPAC Name
(1S,9R,15R,18R,19R,21S,23R,30S,32R,35S)-1,18-dihydroxy-12-[(2S)-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^{4,9}]hexatriaconta-16,24,26,28-tetraene-2,3,10,14,20-pentone
SMILES
CO[C@@H]1C[C@H](C[C@H](C)C2CC(=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](C[C@H]3CC[C@H](C)[C@](O)(O3)C(=O)C(=O)N3CCCC[C@@H]3C(=O)O2)OC)CC[C@H]1OCCO
Mass Specshow(87.7 KB)
Taxonomy
KingdomOrganic Compounds
SuperclassPhenylpropanoids and Polyketides
ClassMacrolide Lactams
SubclassNot Available
Direct parentMacrolide Lactams
Alternative parentsAlpha 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
Substituentspiperidine; 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 descriptionThis compound belongs to the macrolide lactams. These are cyclic polyketides containing both a cyclic amide and a cyclic ester group.
Pharmacology
IndicationEverolimus 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.
PharmacodynamicsNot Available
Mechanism of actionEverolimus 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.
AbsorptionIn 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.
Metabolism

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 eliminationAfter 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.
Clearance

Following a 3 mg radiolabeled dose of everolimus, 80% of the radioactivity was recovered from the feces, while 5% was excreted in the urine.

ToxicityIC50 of 0.63 nM.
Affected organisms
  • Humans and other mammals
PathwaysNot Available
SNP Mediated EffectsNot Available
SNP Mediated Adverse Drug ReactionsNot Available
ADMET
Predicted ADMET features
Property Value Probability
Human Intestinal Absorption - 0.8288
Blood Brain Barrier - 0.9541
Caco-2 permeable - 0.6604
P-glycoprotein substrate Substrate 0.8117
P-glycoprotein inhibitor I Inhibitor 0.7789
P-glycoprotein inhibitor II Inhibitor 0.7294
Renal organic cation transporter Non-inhibitor 0.796
CYP450 2C9 substrate Non-substrate 0.8793
CYP450 2D6 substrate Non-substrate 0.9116
CYP450 3A4 substrate Substrate 0.7407
CYP450 1A2 substrate Non-inhibitor 0.9078
CYP450 2C9 substrate Non-inhibitor 0.9106
CYP450 2D6 substrate Non-inhibitor 0.9388
CYP450 2C19 substrate Non-inhibitor 0.9346
CYP450 3A4 substrate Non-inhibitor 0.8168
CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.9734
Ames test Non AMES toxic 0.6227
Carcinogenicity Non-carcinogens 0.9362
Biodegradation Not ready biodegradable 0.9257
Rat acute toxicity 2.7442 LD50, mol/kg Not applicable
hERG inhibition (predictor I) Weak inhibitor 0.9776
hERG inhibition (predictor II) Non-inhibitor 0.712
Pharmacoeconomics
Manufacturers
  • Novartis pharmaceuticals corp
Packagers
Dosage forms
FormRouteStrength
TabletOral10 mg
TabletOral2.5 mg
TabletOral5.0 mg
TabletOral7.5 mg
Tablet, for suspensionOral2 mg
Tablet, for suspensionOral3 mg
Tablet, for suspensionOral5 mg
Prices
Unit descriptionCostUnit
Afinitor 10 mg tablet247.58USDtablet
Afinitor 5 mg tablet234.75USDtablet
Vesicare 10 mg tablet6.98USDtablet
Vesicare 5 mg tablet6.98USDtablet
DrugBank does not sell nor buy drugs. Pricing information is supplied for informational purposes only.
Patents
CountryPatent NumberApprovedExpires (estimated)
United States72977031999-12-062019-12-06
United States64409901993-09-242013-09-24
Canada21453832004-11-162013-09-24
Canada22259602004-05-112016-07-12
Properties
Statesolid
Experimental PropertiesNot Available
Predicted Properties
PropertyValueSource
Water Solubility0.00163ALOGPS
logP5.01ALOGPS
logP7.4ChemAxon
logS-5.8ALOGPS
pKa (Strongest Acidic)9.96ChemAxon
pKa (Strongest Basic)-2.7ChemAxon
Physiological Charge0ChemAxon
Hydrogen Acceptor Count13ChemAxon
Hydrogen Donor Count3ChemAxon
Polar Surface Area204.66 Å2ChemAxon
Rotatable Bond Count9ChemAxon
Refractivity261.71 m3·mol-1ChemAxon
Polarizability105.73 Å3ChemAxon
Number of Rings4ChemAxon
Bioavailability0ChemAxon
Rule of FiveNoChemAxon
Ghose FilterNoChemAxon
Veber's RuleNoChemAxon
MDDR-like RuleYesChemAxon
Spectra
SpectraNot Available
References
Synthesis Reference
  1. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/001038/WC500022817.pdf
General Reference
  1. Kuhn B, Jacobsen W, Christians U, Benet LZ, Kollman PA: Metabolism of sirolimus and its derivative everolimus by cytochrome P450 3A4: insights from docking, molecular dynamics, and quantum chemical calculations. J Med Chem. 2001 Jun 7;44(12):2027-34. Pubmed
  2. Pubmed
  3. Pubmed
  4. Pubmed
External Links
ResourceLink
KEGG DrugD02714
Therapeutic Targets DatabaseDAP001223
PharmGKBPA164746311
RxListhttp://www.rxlist.com/afinitor-drug.htm
Drugs.comhttp://www.drugs.com/cdi/everolimus.html
WikipediaEverolimus
ATC CodesL04AA18L01XE10
AHFS CodesNot Available
PDB EntriesNot Available
FDA labelshow(548 KB)
MSDSshow(220 KB)
Interactions
Drug Interactions
Drug
BicalutamideCYP3A4 Inhibitors like bicalutamide may increase the serum concentration of everolimus. Consider therapy modification. Recommendations regarding optimal management of this interaction vary according to specific indication and product used.
ClarithromycinThe macrolide, clarithromycin, may increase the serum concentration and toxicity of everolimus.
ClotrimazoleCYP3A4 Inhibitors (Moderate)such as clotrimazole may increase the serum concentration of everolimus. The prescribing information for the Afinitor branded everolimus product lists indication-specific recommendations for managing this interaction.
ConivaptanCYP3A4 Inhibitors (Strong) may increase the serum concentration of Everolimus. Everolimus prescribing information recommends avoiding concurrent use with strong CYP3A4 inhbitors.
ErythromycinThe macrolide, erythromycin, may increase the serum concentration and toxicity of everolimus.
EtravirineEverolimus, when administered concomitantly with etravirine (a strong CYP3A4 inducer), may experience a decrease in serum concentration. It is recommended to avoid this combination. If concurrent therapy cannot be avoided, a gradual dosage increase of everolimus is recommended.
FluconazoleFluconazole may increase everolimus levels/toxicity.
ItraconazoleItraconazole may increase everolimus levels/toxicity.
KetoconazoleKetoconazole may increase everolimus levels/toxicity.
Rilonaceptresults in increased immunosuppressive effects; increases the risk of infection.
VerapamilConcomitant administration may increase the serum concentrations of both agents. Concurrent use should be avoided.
VoriconazoleVoriconzole, a strong CYP3A4 inhibitor, may increase the serum concentration of everolimus by decreasing its metabolism. Concurrent therapy should be avoided.
Food InteractionsNot Available

Targets

1. Serine/threonine-protein kinase mTOR

Kind: protein

Organism: Human

Pharmacological action: yes

Actions: inhibitor

Components

Name UniProt ID Details
Serine/threonine-protein kinase mTOR P42345 Details

References:

  1. 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
  2. Rostaing L, Kamar N: mTOR inhibitor/proliferation signal inhibitors: entering or leaving the field? J Nephrol. 2010 Mar-Apr;23(2):133-42. Pubmed
  3. 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
  4. 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
  5. 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
  6. 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
  7. Chen X, Ji ZL, Chen YZ: TTD: Therapeutic Target Database. Nucleic Acids Res. 2002 Jan 1;30(1):412-5. Pubmed

Enzymes

1. Cytochrome P450 3A4

Kind: protein

Organism: Human

Pharmacological action: unknown

Actions: substrate

Components

Name UniProt ID Details
Cytochrome P450 3A4 P08684 Details

References:

  1. 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

Comments
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Drug created on August 29, 2007 09:37 / Updated on September 16, 2013 17:15