Drug/Small Molecule:
everolimus

PharmGKB contains no dosing guidelines for this drug/small molecule. To report known genotype-based dosing guidelines, or if you are interested in developing guidelines, click here.

PharmGKB annotates drug labels containing pharmacogenetic information approved by the US Food and Drug Administration (FDA), European Medicines Agency (EMA) and the Pharmaceuticals and Medical Devices Agency, Japan (PMDA). PharmGKB annotations provide a brief summary of the PGx in the label, an excerpt from the label and a downloadable highlighted label PDF file. A list of genes and phenotypes found within the label is mapped to label section headers and listed at the end of each annotation. PharmGKB also attempts to interpret the level of action implied in each label with the "PGx Level" tag.

Sources:

  • FDA Information is gathered from the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels" and from FDA-approved labels brought to our attention. Please note that drugs may be removed from or added to the FDA's Table without our knowledge. We periodically check the Table for changes and update PharmGKB accordingly. Drugs listed on the Table to our knowledge are tagged with the Biomarker icon. A drug label that has been removed from the Table will not have the Biomarker icon but will continue to have an annotation on PharmGKB stating the label has been removed from the FDA's Table. We acquire label PDF files from DailyMed.
  • EMA European Public Assessment Reports (EPARs) that contain PGx information were identified from [Article:24433361] and also by searching for drugs for which we have PGx-containing FDA drug labels.

We welcome any information regarding drug labels containing PGx information approved by the FDA, EMA, PMDA or other Medicine Agencies around the world - please contact feedback.



last updated 12/17/2013

FDA Label for everolimus and ERBB2, ESR1

Genetic testing required

Summary

Everolimus (AFINITOR) is indicated for treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane, after failure of treatment with letrozole or anastrozole. It is also indicated for adults with neuroendocrine tumors of pancreatic origin or advanced renal cell carcinoma.

Annotation

Excerpt from the FDA-approved everolimus (AFINITOR) drug label:

AFINITOR is a kinase inhibitor indicated for the treatment of postmenopausal women with advanced hormone receptor-positive, HER2-negative breast cancer in combination with exemestane after failure of treatment with letrozole or anastrozole.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the everolimus drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Full label available at DailyMed

Genes and/or phenotypes found in this label

  • Kidney Neoplasms
    • Indications & usage section, Warnings section, Adverse reactions section
    • source: PHONT
  • Neoplasms
    • Indications & usage section, Contraindications section, Warnings section, Adverse reactions section
    • source: PHONT
  • AKT1
    • Clinical pharmacology section
    • source: FDA Label
  • CYP2D6
    • Clinical pharmacology section
    • source: FDA Label
  • CYP3A4
    • Dosage & administration section, Drug interactions section, Clinical pharmacology section, Warnings and precautions section, toxicity
    • source: FDA Label
  • ERBB2
    • Indications & usage section, Dosage & administration section, Drug interactions section, Adverse reactions section, Clinical pharmacology section, Clinical studies section, Warnings and precautions section, efficacy
    • source: FDA Label
  • FKBP1A
    • Clinical pharmacology section
    • source: FDA Label
  • HIF1A
    • Clinical pharmacology section
    • source: FDA Label
  • MTOR
    • Clinical pharmacology section
    • source: FDA Label
  • PIK3CA
    • Clinical pharmacology section
    • source: FDA Label
  • RPS6KB1
    • Clinical pharmacology section
    • source: FDA Label
  • TSC1
    • Clinical pharmacology section
    • source: FDA Label
  • TSC2
    • Clinical pharmacology section
    • source: FDA Label

last updated 10/25/2013

European Medicines Agency (EMA) Label for everolimus and ERBB2

Actionable PGx

Summary

The EMA European Public Assessment Report (EPAR) for everolimus (Afinitor) contains biomarker information regarding the indication in postmenopausal women with oestrogen receptor-positive, HER2/neu negative advanced breast cancer. It is also indicated in patients with Neuroendocrine tumors of pancreatic origin or advanced renal cell carcinoma.

Annotation

Excerpt from the everolimus (Afinitor) EPAR:

Therapeutic indications
Hormone receptor-positive advanced breast cancer Afinitor is indicated for the treatment of hormone receptor-positive, HER2/neu negative advanced breast cancer, in combination with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor.

This information is highlighted in the following sections:
Therapeutic indications, package leaflet: information for the user.

Also provided is information regarding the metabolism of everolimus by CYP3A4 and PgP (ABCB1) and differences in oral clearance between patients of different ethnicity.

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the everolimus EMA drug label.

*Disclaimer: The contents of this page have not been endorsed by the EMA and are the sole responsibility of PharmGKB.


PharmGKB contains no Clinical Variants that meet the highest level of criteria.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

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This is a non-comprehensive list of genetic tests with pharmacogenetics relevance, typically submitted by the manufacturer and manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.

A more complete listing of genetic tests is found at the Genetic Testing Registry (GTR).

PGx Test Variants Assayed Gene?

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page.

Links in the "Gene" column lead to PharmGKB Gene Pages.

List of all everolimus variant annotations

Gene ? Variant?
(142)
Alternate Names ? Drugs ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available No VIP available VA CYP2C8 *1A N/A N/A N/A
No VIP available No VIP available VA CYP2C8 *3 N/A N/A N/A
No VIP available No VIP available VA CYP3A4 *1 N/A N/A N/A
No VIP available No VIP available VA CYP3A4 *22 N/A N/A N/A
No VIP available No VIP available VA CYP3A5 *1A N/A N/A N/A
No VIP available No VIP available VA CYP3A5 *3A N/A N/A N/A
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 142

Overview

Generic Names
  • everolimus
Trade Names
  • Afinitor
  • Certican
Brand Mixture Names

PharmGKB Accession Id:
PA164746311

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.

Source: Drug Bank

Indication

Investigated for use/treatment in transplant (rejection) and renal cell carcinoma.

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

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.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

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.

Source: Drug Bank

Chemical Properties

Chemical Formula

C53H83NO14

Source: Drug Bank

Isomeric SMILES

C[C@@H]1CC[C@H]2C[C@@H](/C(=C/C=C\C=C\[C@H](C[C@H](C(=O)[C@@H]([C@@H](/C(=C\[C@H](C(=O)C[C@H](OC(=O)[C@@H]3CCCCN3C(=O)C(=O)[C@@]1(O2)O)[C@H](C)C[C@@H]4CC[C@H]([C@@H](C4)OC)OCCO)C)/C)O)OC)C)C)/C)OC

Source: Drug Bank

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

Source: Drug Bank

Canonical SMILES

CO[C@@H]1C[C@H]

Source: Drug Bank

Average Molecular Weight

958.2244

Source: Drug Bank

Monoisotopic Molecular Weight

957.581356369

Source: Drug Bank

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

Drug Targets

Gene Description
MTOR (source: Drug Bank)

Drug Interactions

Drug Description
everolimus The macrolide, clarithromycin, may increase the serum concentration and toxicity of everolimus. (source: Drug Bank)
everolimus The macrolide, erythromycin, may increase the serum concentration and toxicity of everolimus. (source: Drug Bank)
everolimus The imidazole increases everolimus levels/toxicity (source: Drug Bank)
everolimus The imidazole increases everolimus levels/toxicity (source: Drug Bank)
everolimus The imidazole increases everolimus levels/toxicity (source: Drug Bank)
everolimus The imidazole increases everolimus levels/toxicity (source: Drug Bank)
everolimus Concomitant administration may increase the serum concentrations of both agents. Concurrent use should be avoided. (source: Drug Bank)
everolimus Voriconzole, a strong CYP3A4 inhibitor, may increase the serum concentration of everolimus by decreasing its metabolism. Concurrent therapy should be avoided. (source: Drug Bank)

Curated Information ?

Publications related to everolimus: 6

No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Effect of CYP3A4*22, CYP3A5*3, and CYP3A Combined Genotypes on Cyclosporine, Everolimus, and Tacrolimus Pharmacokinetics in Renal Transplantation. CPT: pharmacometrics & systems pharmacology. 2014. Moes D J A R, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Emerging landscape of oncogenic signatures across human cancers. Nature genetics. 2013. Ciriello Giovanni, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
The role of CYP2C8 genotypes in dose requirement and levels of everolimus after heart transplantation. Wiener klinische Wochenschrift. 2013. Kniepeiss Daniela, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Interaction of sirolimus and everolimus with hepatic and intestinal organic anion-transporting polypeptide transporters. Xenobiotica; the fate of foreign compounds in biological systems. 2011. Picard Nicolas, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
The role of CYP3A5 genotypes in dose requirements of tacrolimus and everolimus after heart transplantation. Clinical transplantation. 2011. Kniepeiss Daniela, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Evolving novel anti-HER2 strategies. The lancet oncology. 2009. Jones Kellie L, et al. PubMed

LinkOuts

Web Resource:
Wikipedia
National Drug Code Directory:
0078-0417-20
DrugBank:
DB01590
PubChem Compound:
6442177
PubChem Substance:
12014881
Therapeutic Targets Database:
DAP001223
FDA Drug Label at DailyMed:
e082a024-7850-400b-a5c2-2a140612562a

Clinical Trials

These are trials that mention everolimus and are related to either pharmacogenetics or pharmacogenomics.

Common Searches

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Sources for PharmGKB drug information: DrugBank, Open Eye Scientific Software.