Novartis’ Afinitor (everolimus) was approved by the FDA on February 26, 2016, for the treatment of adult patients with unresectable, locally advanced or metastatic progressive, well-differentiated non-functional neuroendocrine tumors (NETs) originating from the gastrointestinal or lung areas.
Afinitor, also known as everolimus, is a type of medication categorized as an mTOR inhibitor. It is available in tablet form and functions by restraining the activity of a protein called mammalian target of rapamycin (mTOR) in cells, ultimately slowing the growth and spread of cancerous cells.
Afinitor is a treatment option for various types of cancer, such as breast cancer, kidney cancer, pancreatic cancer, and lung cancer.
Afinitor (Everolimus) MOA (mechanism of action):
Everolimus, a medication belonging to the mTOR inhibitors class, acts by inhibiting the mTOR pathway, a significant regulator of cell growth and metabolism.
The mTOR pathway is responsible for regulating various cellular processes, including protein synthesis, cell growth, and survival.
In normal cells, the mTOR pathway is tightly regulated to ensure that the cell is functioning appropriately.
However, in cancer cells, this pathway is frequently upregulated, leading to uncontrolled growth and division, a hallmark of cancer.
mTOR is a protein kinase, an enzyme that phosphorylates proteins, located in the cytoplasm of the cell. It forms two protein complexes, mTORC1 and mTORC2, each with distinct functions.
mTORC1 regulates protein synthesis, cell growth, and metabolism, while mTORC2 is involved in cell survival and cytoskeletal organization.
Both complexes are essential in cancer cell growth and proliferation, making mTOR a significant therapeutic target.
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Everolimus inhibits the activity of mTORC1 by binding to a protein called FKBP12. This complex then binds to mTORC1, inhibiting its activity and reducing the production of proteins that are necessary for cell growth and division.
Everolimus does not inhibit mTORC2 directly, but the inhibition of mTORC1 may affect its activity indirectly.
Several studies have demonstrated the efficacy of Everolimus in the treatment of various types of cancer.
For instance, it has been approved for the treatment of hormone receptor-positive, and HER2-negative breast cancer in combination with exemestane, and for the treatment of advanced renal cell carcinoma.
Moreover, it has shown promise in treating other types of cancer, such as neuroendocrine tumors, pancreatic cancer, and non-small cell lung cancer.
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Below is a table summarizing the main cellular processes regulated by the mTOR pathway and the effects of Everolimus inhibition.
Cellular process | Role of mTOR pathway | Effect of Everolimus Inhibition |
| Protein synthesis | Regulates protein synthesis and ribosome biogenesis | Inhibition of protein synthesis |
| Cell growth | Stimulates cell growth and proliferation | Inhibition of cell growth |
| Cell metabolism | Regulates metabolism, including glucose uptake and lipid synthesis | Inhibition of metabolism |
| Cell survival | Promotes cell survival | Indirect inhibition through mTORC1 inhibition |
Pharmacodynamics of mTOR Inhibitor Everolimus:
Everolimus functions by inhibiting the mTOR protein kinase, which plays a crucial role in regulating cell growth, metabolism, and survival.
The mTOR pathway is the therapeutic target of Everolimus, and its inhibition leads to a reduction in the growth and spread of cancerous cells.
Everolimus has been approved for treating advanced renal cell carcinoma, pancreatic neuroendocrine tumors, breast cancer, subependymal giant cell astrocytoma, and mantle cell lymphoma.
However, it’s important to note that individual patient factors like age, weight, and medical history may affect the drug’s pharmacodynamics and should be closely monitored.
Pharmacokinetics of mTOR Inhibitor Everolimus:
Everolimus is rapidly absorbed after oral administration and has a low bioavailability due to extensive first-pass metabolism in the liver.
It is widely distributed throughout the body, with most of it bound to plasma proteins.
Everolimus is metabolized in the liver by the CYP3A4 enzyme, which produces metabolites with less activity than the parent drug.
The drug is eliminated through feces (70%) and urine (13%), with a half-life of around 30 hours.
The metabolism and elimination of Everolimus can be affected by strong CYP3A4 inhibitors and inducers, leading to increased or decreased blood levels. As a result, monitoring the patient’s pharmacokinetics is essential.
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Everolimus (Afinitor) Indications and Dosage:
To treat different types of cancer, Everolimus is indicated for various conditions, including:
- advanced renal cell carcinoma,
- neuroendocrine tumors,
- breast cancer,
- subependymal giant cell astrocytoma, and
- mantle cell lymphoma.
The dosage and administration of Everolimus may vary depending on the patient’s medical history, age, weight, and other factors.
The recommended starting dose of Everolimus is 10 mg once daily, which can be taken with or without food, depending on the patient’s condition. The tablets are available in different strengths 2.5 mg, 5 mg, 7.5 mg, and 10 mg.
For advanced renal cell carcinoma, the recommended dose is 10 mg once daily, either with or without food.
For PNETs, the recommended starting dose is 10 mg once daily, with or without food.
For breast cancer, the recommended dose is 10 mg once daily in combination with exemestane.
For SEGA, the recommended dose is 4.5 mg/m2 once daily, with or without food.
For MCL, the recommended dose is 10 mg once daily, with or without food.
It’s essential to note that the recommended dosage may vary based on individual patient factors such as response to treatment and tolerability.
Therefore, the patient’s condition should be closely monitored while on Everolimus therapy.
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Side Effects of Everolimus (Afinitor):
Common Side Effects:
Side Effect | Description |
| Mouth ulcers | Sores in the mouth or on the lips |
| Diarrhea | Loose, watery stools |
| Nausea and vomiting | Feeling sick and vomiting |
| Loss of appetite | Decreased desire to eat or drink |
| Headache | Pain or discomfort in the head |
| Fatigue | Feeling tired or weak |
| Rash or itchy skin | Redness or itching of the skin |
| Anemia | Decrease in red blood cells, causing fatigue |
| High blood sugar | Elevated blood sugar levels |
| Elevated liver enzymes | Abnormal liver function tests |
Serious Side Effects:
Side Effect | Description |
| Infections | Increased risk of infections, including opportunistic |
| Lung problems | Inflammation of the lungs, cough, difficulty breathing |
| Kidney problems | Affects kidney function, decrease in urine output |
| Blood disorders | Decrease in the number of white and red blood cells |
| Delayed wound healing | Delay in the healing of wounds |
| Increased risk of bleeding | Increased risk of bleeding, especially if taking blood thinners |
| Hyperglycemia | Elevated blood sugar levels, leading to diabetes |
| Interactions with other medications | Interactions with other medications, lead to increased side effects or decreased efficacy |
It is important to inform your doctor about any medical conditions or medications you are taking before starting treatment with Everolimus.
Like all medications, Everolimus can cause side effects, some of which can be serious. Patients should discuss the benefits and risks of treatment with Everolimus with their healthcare provider before starting treatment.