Everolimus is a Kinase Inhibitor and mTOR Inhibitor Immunosuppressant. The mechanism of action of everolimus is as a Protein Kinase Inhibitor and Cytochrome P450 3A4 Inhibitor and P-Glycoprotein Inhibitor and Cytochrome P450 2D6 Inhibitor and mTOR Inhibitor. The physiologic effect of everolimus is by means of Decreased Immunologic Activity.
Everolimus is a derivative of the natural macrocyclic lactone sirolimus with immunosuppressant and anti-angiogenic properties. In cells, everolimus binds to the immunophilin FK Binding Protein-12 (FKBP-12) to generate an immunosuppressive complex that binds to and inhibits the activation of the mammalian Target of Rapamycin (mTOR), a key regulatory kinase. Inhibition of mTOR activation results in the inhibition of T lymphocyte activation and proliferation associated with antigen and cytokine (IL-2, IL-4, and IL-15) stimulation and the inhibition of antibody production. (NCI05)
Mechanism of Action of Everolimus
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.
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Mechanistic target of rapamycin (mTOR) is a serine–threonine kinase that functions via two multiprotein complexes, namely mTORC1 and mTORC2, each characterized by different binding partners that confer separate functions. mTORC1 function is tightly regulated by PI3-K/Akt and is sensitive to rapamycin. mTORC2 is sensitive to growth factors, not nutrients, and is associated with rapamycin-insensitivity. mTORC1 regulates protein synthesis and cell growth through downstream molecules: 4E-BP1 (also called EIF4E-BP1) and S6K. Also, mTORC2 is thought to modulate growth factor signaling by phosphorylating the C-terminal hydrophobic motif of some AGC kinases such as Akt and SGK. Recent evidence has suggested that mTORC2 may play an important role in maintenance of normal as well as cancer cells by virtue of its association with ribosomes, which may be involved in metabolic regulation of the cell. Rapamycin (sirolimus) and its analogs known as rapalogues, such as RAD001 (everolimus) and CCI-779 (temsirolimus), suppress mTOR activity through an allosteric mechanism that acts at a distance from the ATP-catalytic binding site, and are considered incomplete inhibitors. Moreover, these compounds suppress mTORC1-mediated S6K activation, thereby blocking a negative feedback loop, leading to activation of mitogenic pathways promoting cell survival and growth. Consequently, mTOR is a suitable target of therapy in cancer treatments. However, neither of these complexes is fully inhibited by the allosteric inhibitor rapamycin or its analogs. In recent years, new pharmacologic agents have been developed which can inhibit these complexes via ATP-binding mechanism, or dual inhibition of the canonical PI3-K/Akt/mTOR signaling pathway. These compounds include WYE-354, KU-003679, PI-103, Torin1, and Torin2, which can target both complexes or serve as a dual inhibitor for PI3-K/mTOR. This investigation describes the mechanism of action of pharmacological agents that effectively target mTORC1 and mTORC2 resulting in suppression of growth, proliferation, and migration of tumor and cancer stem cells.
Indications of Everolimus
- 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 the 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.
- Breast Cancer
- Renal Cell Carcinoma
- Pancreatic Cancer
- Renal Angiomyolipoma
- Neuroendocrine Carcinoma
- Brain/Intracranial Tumor
- Organ Transplant
- Seizures
FDA Level
- 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.
- 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 nonsteroidal aromatase inhibitor.
- Neuroendocrine tumors of pancreatic origin. Afinitor is indicated for the treatment of unresectable or metastatic, well or moderately differentiated neuroendocrine tumors of pancreatic origin in adults with the progressive disease.
- Neuroendocrine tumors of gastrointestinal or lung origin. Afinitor is indicated for the treatment of unresectable or metastatic, well-differentiated (Grade 1 or Grade 2) non-functional neuroendocrine tumors of gastrointestinal or lung origin in adults with progressive disease (see sections 4.4 and 5.1).
- Renal cell carcinoma. Afinitor is indicated for the treatment of patients with advanced renal cell carcinoma, whose disease has progressed on or after treatment with VEGF targeted therapy.
- Treatment of renal cell carcinoma
- Treatment of tuberous sclerosis
- Treatment of gastro-entero-pancreatic neuroendocrine tumors
- Renal angiomyolipoma associated with tuberous sclerosis complex (TSC)
Contra-Indications of Everolimus
- Severe infection
- Malignant tumor or cancer
- Diabetes
- High cholesterol
- High amount of triglyceride in the blood
- Syndrome characterized by Anemia and Renal Failure
- Anemia
- Decreased Blood Platelets
- Decreased white blood cells
- Fluid in the Covering of the Heart or Pericardium
- Thrombotic Thrombocytopenic Purpura
- Escape of Fluid into the Lungs
- Interstitial Pneumonitis
- Painful
- Red or Swollen Mouth
- Liver problems
- Acute kidneyl failure
- Blood Clot in an Artery of the Kidney
- Visible Water Retention
- Ascites
- High Blood Sugar
- Elevation of Proteins in the Urine
- Impaired Wound Healing
- Pregnancy
- A mother who is producing milk and breastfeeding
- Malignant Lymphoma
- Blood Clot in Artery of Liver Following Liver Transplant
- Heart Transplant
- BK Virus Reactivation causing Kidney Problems
- Allergies to Macrolide Immunosuppressant
Dosage of Everolimus
Strengths: 0.5 mg; 0.75 mg; 0.25 mg; 5 mg; 10 mg; 2.5 mg; 7.5 mg; 2 mg; 3 mg
Breast Cancer
- 10 mg orally once a day
- Duration of therapy: Continue until disease progression or unacceptable toxicity occurs.
Renal Cell Carcinoma
- 10 mg orally once a day
- Duration of therapy: Continue until disease progression or unacceptable toxicity occurs.
Pancreatic Cancer
- 10 mg orally once a day
- Duration of therapy: Continue until disease progression or unacceptable toxicity occurs.
Brain/Intracranial Tumor
- 4.5 mg/m2 orally once a day
- Duration of therapy: Continue until disease progression or unacceptable toxicity occurs. The optimal duration of therapy is unknown.
Side Effects of Everolimus
The Most Common
- agitation
- changes to menstrual cycles
- changes in sense of taste
- constipation
- cough
- dehydration (e.g., decreased urine, dry skin, dry and sticky mouth, sleepiness, dizziness, headache, thirst, confusion)
- diarrhea
- difficulty sleeping
- difficulty swallowing
- dizziness
- dry mouth
- gum swelling
- hair loss
- headache
- loss of appetite
More Common
- Bloating or swelling of the face, arms, hands, lower legs, or feet
- bloody nose
- chest pain or tightness
- chills
- cough
- decreased weight
- diarrhea
- difficult or labored breathing
- difficulty with swallowing
- fever
- general feeling of discomfort or illness
- hoarseness
- lower back or side pain
- painful or difficult urination
- rapid weight gain
- sores, ulcers, or white spots on the lips, tongue, or inside the mouth
Rare
- rash on the palms of the hands and soles of the feet
- signs of anemia (low red blood cells; e.g., dizziness, pale skin, unusual tiredness or weakness, shortness of breath)
- signs of clotting problems (e.g., unusual nosebleeds, bruising, blood in urine, coughing blood, bleeding gums, cuts that don’t stop bleeding)
- signs of a blood clot in blood vessels, such as sudden vision change or dizziness, chest pain, pain and swelling in one leg muscle
- signs of fluid build-up around the lungs (e.g., chest pain, cough, hiccups, rapid breathing)
- signs of infection (symptoms may include fever or chills, severe diarrhea, shortness of breath, prolonged dizziness, headache, stiff neck, weight loss, or listlessness)
- signs of kidney failure (e.g., decreased urine production, swelling, fatigue, abdominal pain)
- signs of liver problems (e.g., nausea, vomiting, diarrhea, loss of appetite, weight loss, yellowing of the skin or whites of the eyes, dark urine, pale stools)
- signs of low potassium levels in the blood (e.g., weakness, fatigue, muscle cramps, irregular heartbeat)
- swelling in the hands, feet, ankles, face
- symptoms of high blood sugar (e.g., frequent urination, increased thirst, excessive eating, unexplained weight loss, poor wound healing, infections, fruity breath odour)
Drug Interactions of Everolimus
Everolimus interact with following drugs, supplements & may change the efficacy of drugs
- Angiotensin-converting enzyme inhibitors (ACEIs; e.g., captopril, lisinopril, ramipril)
- atorvastatin
- “azole” antifungals (e.g., itraconazole, ketoconazole, voriconazole)
- BCG vaccine
- calcium channel blockers (e.g., diltiazem, nicardipine, verapamil)
- carbamazepine
- carvedilol
- cimetidine
- clozapine
- cyclosporine
- desipramine
- dexamethasone
- diabetes medications (e.g., chlorpropamide, glipizide, glyburide, insulin, metformin, rosiglitazone)
- hepatitis protease inhibitors (e.g., boceprevir, simeprevir)
- fosphenytoin
- grapefruit juice
- haloperidol
- HIV non-nucleoside reverse transcriptase inhibitors (NNRTIs; e.g., delavirdine, efavirenz, etravirine, nevirapine)
- HIV protease inhibitors (atazanavir, darunavir, lopinavir, ritonavir)
- macrolide antibiotics (e.g., azithromycin, clarithromycin, erythromycin)
- metronidazole
- mifepristone
- mirabegron
- modafinil
- norfloxacin
- oxcarbazepine
- pentobarbital
- phenobarbital
- phenytoin
- prazosin
- progesterone
- propranolol
- protein kinase inhibitors (e.g., crizotinib, dabrafenib, imatinib, lapatinib, nilotinib)
- St. John’s Wort
- tacrolimus
- tamoxifen
- tocilizumab
- trastuzumab
Pregnancy Category
AU TGA pregnancy category: C
US FDA pregnancy category: N (Not assigned)
Pregnancy
Everolimus may cause harm to an unborn baby. Women who may become pregnant while taking this medication must use an effective form of birth control, even if they have not had their first menstrual period. Effective birth control must be used during treatment with everolimus, and for at least eight weeks following the discontinuation of treatment. If you become pregnant while taking this medication, contact your doctor immediately.
Lactation
It is not known if everolimus passes into breast milk. If you are a breast-feeding mother and are taking this medication, it may affect your baby. Talk to your doctor about whether you should continue breastfeeding. Everolimus is not recommended for children with cancer who are less than 18 years of age. The safety and effectiveness of using this medication have not been studied for children with SEGA who are less than 1 year of age and there is limited information about the use of everolimus for children less than 3 years of age.
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