Everolimus

Introduction Overview

Generic Name

everolimus

Brand Name

Afinitor

Dosage Form

oral tablet, dispersible tablet

Drug Class

mTOR inhibitors, Selective immunosuppressants

Pharmacokinetics

Absorption

Everolimus (Afinitor) is rapidly absorbed after oral administration, with peak plasma concentrations typically reached within 1 to 2 hours. Food intake can reduce the rate and extent of absorption; it is recommended to take the drug consistently either with or without food to maintain steady plasma levels. The absolute bioavailability of everolimus tablets is approximately 30%. Extensive first-pass metabolism occurs, affecting oral bioavailability. Absorption is influenced by gastrointestinal pH and motility, and concomitant use of agents affecting CYP3A4 or P-glycoprotein can alter absorption dynamics.

Distribution

Everolimus is extensively distributed throughout the body, with a large volume of distribution estimated around 100 L, indicating tissue binding beyond the vascular compartment. It is highly protein-bound (~74%), primarily to plasma albumin and alpha-1 acid glycoprotein. Everolimus penetrates various tissues including tumor sites, which contributes to its therapeutic effects. It crosses the blood-brain barrier to some extent, supporting its use in brain tumors. Distribution can be affected by changes in plasma protein levels in certain disease states.

Metabolism

Everolimus undergoes extensive hepatic metabolism, predominantly via the cytochrome P450 enzyme CYP3A4 and the efflux transporter P-glycoprotein (P-gp). The metabolism produces several metabolites, none of which are pharmacologically active. The metabolic clearance is subject to significant drug-drug interactions, especially with CYP3A4 inducers or inhibitors. Genetic polymorphisms in CYP3A4 may influence metabolism rates. Hepatic impairment can reduce metabolic clearance, necessitating dose adjustments.

Elimination

Everolimus elimination occurs primarily via the feces, with approximately 80% of the administered dose excreted in feces mostly as metabolites, and around 5% recovered unchanged in urine. The terminal half-life is approximately 30 hours, supporting once-daily dosing. Renal elimination is minimal. Clearance can be altered by hepatic function and concomitant medications. Dose modifications may be required in patients with hepatic impairment to avoid toxicity.

Dosage Forms

Adults

Afinitor is available as oral immediate-release tablets and dispersible tablets for oral suspension. The tablets are intended for once-daily administration with doses tailored according to indication and patient tolerability. Adult dosing varies from 5 mg to 10 mg once daily, with specific regimens for different cancers and conditions such as advanced renal cell carcinoma, hormone receptor-positive breast cancer, and neuroendocrine tumors. Dose adjustments may be required based on toxicities and therapeutic response.

Adolescents

In pediatric and adolescent patients with tuberous sclerosis complex-associated tumors or seizures, dosing is carefully individualized often based on body surface area, typically ranging from 4.5 mg/m² to 5 mg/m² once daily. The dispersible tablet formulation is preferred in younger patients for ease of administration. Monitoring and dose titration are essential to balance efficacy and adverse effects.

Special Populations

Special populations such as patients with hepatic impairment require dose reduction due to decreased clearance. Renal impairment generally does not necessitate dosage adjustment. Elderly patients should be monitored closely for side effects, although no specific dosing changes are mandated solely on age. Patients with a history of infections or compromised immune systems need careful evaluation. Breastfeeding is contraindicated during therapy and for at least two weeks after cessation due to potential secretion of the drug in breast milk.

Mechanism Of Action

Everolimus is a selective inhibitor of the mammalian target of rapamycin (mTOR), a serine/threonine kinase crucial for regulating cell growth, proliferation, metabolism, and survival. By binding to the intracellular protein FKBP-12, everolimus forms a complex that directly inhibits mTOR Complex 1 (mTORC1), leading to blockage of downstream signaling pathways. This inhibition decreases protein synthesis and cell cycle progression, resulting in antiproliferative and antiangiogenic effects. Importantly, everolimus impairs cancer cell growth and induces cell cycle arrest at the G1 phase, contributing to its therapeutic efficacy against various tumors. At the molecular level, it reduces phosphorylation of key proteins such as p70 S6 kinase and 4E-BP1, which are essential for protein translation initiation. Clinically, this mechanism translates into slowing tumor growth and reducing tumor vascularization, which can be critical in advanced cancers and tuberous sclerosis complex-related lesions. Comparative studies show everolimus has improved pharmacokinetics and oral bioavailability relative to rapamycin, enhancing its clinical utility. Moreover, its immunosuppressive properties, via mTOR inhibition, modulate T-cell proliferation, contributing to post-transplant rejection prophylaxis but also increasing infection risk during cancer therapy. Current research explores combination therapies with everolimus to overcome resistance mechanisms and enhance antitumor efficacy, further establishing its role in targeted molecular oncology.

Pharmacological Actions

Inhibits mTOR Complex 1, blocking cell growth and proliferation
Induces cell cycle arrest in tumor cells at the G1 phase
Suppresses angiogenesis by downregulating VEGF expression
Exerts immunosuppressive effects by inhibiting T-cell activation and proliferation
Reduces protein synthesis through inhibition of p70 S6 kinase and 4E-BP1 phosphorylation
Slows tumor growth and progression in various solid tumors
Modulates metabolic processes including glucose and lipid metabolism
Enhances apoptosis in certain cancer cell types under study

Therapeutic Clinical Uses

Treatment of advanced kidney (renal cell) carcinoma after failure of treatment with sunitinib or sorafenib
Treatment of hormone receptor-positive, HER2-negative advanced breast cancer in combination with exemestane after failure of letrozole or anastrozole
Management of progressive neuroendocrine tumors of pancreatic origin that are unresectable or metastatic
Treatment of subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex in patients who require therapeutic intervention but are not candidates for surgery
Management of renal angiomyolipoma associated with tuberous sclerosis complex in patients at risk of complications
Used for certain types of advanced or progressive tumors of the stomach and intestines
Control of seizures or benign tumors in patients with tuberous sclerosis complex
Off-label uses including post-transplant immunosuppression in some cases

Side Or Adverse Effects

Stomatitis including mouth ulcers and mucosal inflammation
Increased risk of infections including bacterial, fungal, and viral types
Non-infectious pneumonitis, presenting as cough, dyspnea, or chest discomfort
Peripheral edema and general body swelling
Hyperglycemia with symptoms such as increased thirst and urination
Dyslipidemia including elevated cholesterol and triglycerides
Fatigue and asthenia
Nausea and loss of appetite leading to weight loss
Rash and other dermatologic reactions
Hepatotoxicity manifesting as elevated liver enzymes and jaundice
Renal impairment with decreased urine output and edema
Cytopenias including anemia, thrombocytopenia, and leukopenia
Delayed wound healing, necessitating temporary drug interruption before surgeries
Rare but serious hypersensitivity reactions including angioedema and anaphylaxis

Precautions

Avoid live vaccines during treatment and for some time afterward due to immunosuppression
Monitor for signs of infection or lung toxicity closely throughout therapy
Regular liver function tests to detect hepatotoxicity early
Adjust dosage in patients with hepatic impairment
Inform patients about potential mouth ulcers and advise on oral hygiene and use of prescribed mouthwashes
Close monitoring of blood glucose and lipid levels to manage metabolic complications
Temporary therapy discontinuation before and after major surgeries to promote wound healing
Counsel female and male patients regarding effective contraception during and after therapy due to teratogenicity
Avoid concomitant use with strong CYP3A4 inhibitors or inducers unless clinically necessary
Pay attention to potential drug interactions that can alter everolimus levels
Evaluate for any history of hepatitis B virus infection as reactivation can occur
Monitor renal function especially in patients with pre-existing renal disease
Screen for pulmonary symptoms indicating non-infectious pneumonitis
Exercise caution in patients with diabetes or hyperlipidemia

Warnings

Potential for serious and fatal infections due to immunosuppression
Risk of non-infectious pneumonitis which can be severe or fatal
Hepatitis B virus reactivation in carriers
Increased risk of impaired wound healing; stop therapy before surgery
Risk of renal failure and proteinuria
Potential teratogenic effects and harm to fetus
Use with caution in patients with pre-existing lung or liver disease
Drug-induced hyperglycemia, sometimes requiring medical intervention
Possible life-threatening hypersensitivity reactions
Avoid live vaccines due to compromised immune response
Monitor for bleeding tendencies, especially in patients on concomitant anticoagulants or antiplatelet agents
Increased risk of malignancies with long-term immunosuppression
Risk of hepatic failure in patients with severe liver disease
May cause infertility or impair fertility in both sexes

Contraindications

Known hypersensitivity to everolimus or analogs like sirolimus or temsirolimus
Pregnancy due to risk of fetal harm
Breastfeeding during treatment and for at least two weeks after cessation
Concurrent use with strong CYP3A4 inhibitors without proper dose adjustment
Patients with active severe infections
Use in patients with uncontrolled diabetes or hyperlipidemia without appropriate medical management
Known hypersensitivity to components of the tablet formulation
Patients unable to comply with adequate contraception measures

Drug Interactions

Strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole) increase everolimus plasma levels, raising toxicity risk
CYP3A4 inducers (e.g., rifampin, phenytoin, St. John's wort) decrease everolimus efficacy by reducing plasma levels
Concomitant use with immunosuppressants like steroids or cytotoxic chemotherapy enhances immunosuppressive effects and infection risk
Interactions with ACE inhibitors may increase risk of angioedema or allergic reactions
Co-administration with certain antifungal and antiviral agents can alter everolimus metabolism
Avoid grapefruit and grapefruit juice as they can increase everolimus plasma concentrations
Drugs that affect P-glycoprotein can modify absorption and clearance
Concomitant use with live vaccines is contraindicated due to potential diminished immune response
Some anti-epileptic drugs may induce metabolism and reduce everolimus effectiveness
Drug interactions may necessitate dose adjustments and increased monitoring
Use with caution when combined with other drugs causing nephrotoxicity or hepatotoxicity
Potential additive risk of hyperglycemia when combined with other diabetogenic drugs

Preparations Of The Drug

Oral immediate-release tablets: available as 2.5 mg, 5 mg, 7.5 mg, and 10 mg strengths
Afinitor Disperz: orally-disintegrating tablet formulation available in 2 mg, 3 mg, 5 mg, 7 mg, and 10 mg for easier administration in pediatric patients
Available commercially in blister packs and bottles with specific storage conditions
Provided with detailed patient information leaflets and dosing instructions
Not available as intravenous formulation for systemic use
Supplied in original packaging protecting from moisture and light