Evermil

Everolimus (Afinitor) instructions

Common name: Everolimus

Trade name: Afinitor

All names: Everolimus, Afinitor, Everolimus, Afinitor

1. Indications of everolimus

Everolimus is suitable for the treatment of the following patients:

(1) Adult patients with advanced renal cell carcinoma who have failed previous treatment with sunitinib or sorafenib.

(2) Adult patients with unresectable, locally advanced or metastatic, well-differentiated (moderately differentiated or highly differentiated) advanced pancreatic neuroendocrine tumors.

(3) Adult and pediatric patients with tuberous sclerosis complex (TSC)-related subependymal giant cell astrocytoma (SEGA) who require therapeutic intervention but are not suitable for surgical resection.

2. Everolimus usage and dosage

This product should be used for treatment under the guidance of a doctor with experience in treating tumors or tuberous sclerosis.

Advanced renal cell carcinoma and advanced pancreatic neuroendocrine tumors

Recommended dose of everolimus:

The recommended dose of this product is 10 mg once daily.

This product is administered orally once a day at the same time every day, with or without food.

3. Adverse reactions of everolimus

Non-infectious pneumonia, infection, oral ulcers, and renal failure.

4. Contraindications of Afinitor

It is prohibited for those who are allergic to the active ingredients of this product, other rapamycin derivatives, or any excipients in this product. Manifestations of allergic reactions that have been observed in patients taking everolimus and other rapamycin derivatives include, but are not limited to: anaphylaxis, dyspnea, flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue with or without respiratory insufficiency).

5. Pharmacology and Toxicology of Afinitor

(1) Pharmacology and Toxicology

General toxicity: The non-clinical safety of everolimus was evaluated in mice, rats, mini pigs, monkeys and rabbits. The main target organs and toxicity manifestations are: degeneration of the testicular vas deferens, decreased sperm content in the epididymis, and uterine atrophy in the male and female reproductive systems of some animal species; an increase in the number of alveolar macrophages in rats and mice; degranulation and vacuolation of pancreatic secretory cells in monkeys and mini pigs, and degeneration of monkey islet cells; and opacity of the anterior lens of the rat eye. Age-related increases in lipofuscin deposition in tubular epithelial cells and minor renal changes with increased hydronephrosis were observed in rats, and minor renal changes with increased injury were observed in mice.

Exacerbations of spontaneous physiological diseases, such as chronic myocarditis in rats, coxsackie virus infection in monkey plasma and heart, gastrointestinal coccidiosis infection in miniature pigs, and skin lesions in mice and monkeys, have been reported with the use of everolimus. These reactions usually occur when systemic exposure levels are within or exceed the therapeutic exposure range. Occurrence occurs at subtherapeutic exposures only in rats due to high tissue distribution.

The results of the toxicity test on young mice show that at doses as low as 0.15 mg/kg/day, dose-related delays in developmental markers can be observed, including delayed eye opening, slow development, and prolonged latency in the learning and memory stages.

Genotoxicity: The results of in vitro tests (Ames test, mouse lymphocytoma L5178Y mutation test, Chinese hamster cell chromosome aberration test) and in vivo tests (mouse bone marrow micronucleus test) did not show that everolimus has genotoxicity.

Reproductive toxicity: Male rat fertility test results showed that testicular morphology was affected at doses of 0.5mg/kg and above. At the 5 mg/kg dose (the exposure at this dose is within the therapeutic exposure range) sperm motility, sperm number, plasma testosterone levels, and fertility were reduced, and the above adverse effects were reversible. Fertility in female rats is not affected, but everolimus can cross the placenta and produce embryotoxicity. Everolimus can cause embryotoxicity/fetal toxicity in rats at systemic exposures below therapeutic levels, manifested by animal death and fetal weight loss. An increased incidence of skeletal changes and deformities (such as sternal clefts) was observed at 0.3 and 0.9 mg/kg. Increased late resorption in rabbits suggests that everolimus is embryotoxic in rabbits.

Carcinogenicity: Everolimus did not show any carcinogenic potential when administered to mice and rats for up to 2 years at doses equivalent to 3.9 times and 0.2 times the estimated clinical exposure, respectively.

(2)Pharmacological effects

Everolimus is a selective inhibitor of mTOR. mTOR is a key serine-threonine kinase whose activity is upregulated in some human tumors. Everolimus can combine with the intracellular protein FKBP12 to form an inhibitory complex mTORC1, which can inhibit the activity of mTOR. Inhibition of the mTOR signaling pathway can lead to a decrease in the activity of the transcription regulator S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4E-BP), thereby interfering with the translation and synthesis of cell cycle, angiogenesis, glycolysis and other related proteins. Everolimus can reduce the expression of vascular endothelial growth factor (VEGF). Everolimus is a potent inhibitor of the growth and proliferation of tumor cells, endothelial cells, fibroblasts, and vascular smooth muscle cells, and can inhibit glycolysis of solid tumors in vivo and in vitro.

6. Afinitor pharmacokinetics

(1) Absorption

In patients with advanced solid tumors, the peak concentration of this product is reached 1-2 hours after oral administration of 5 mg to 70 mg. After a single dose, Cmax is dose proportional between 5 mg and 10 mg. At doses of 20 mg and higher, Cmax increases less than dose proportionally, but AUC is dose proportional in the range of 5 mg-70 mg. Steady state is reached within two weeks after once-daily dosing.

Dose Proportionality in Patients with Tuberous Sclerosis-Related Subependymal Giant Cell Astrocytoma: In patients with tuberous sclerosis-associated subependymal giant cell astrocytoma, the everolimus Cmin was approximately proportional to the dose in the dose range of 1.35 mg/m2 to 14.4 mg/m2.

Food effect: In healthy subjects, a high-fat meal reduced the systemic exposure (AUC) of 10 mg tablets by 22°% and Cmax by 54°%. Low-fat meals reduced AUC by 32°% and Cmax by 42°%. However, food has no significant effect on the drug-time curve in the post-absorption stage.

(2) Distribution

The blood-plasma concentration ratio of everolimus (concentration-dependent in the range of 5-5000ng/ml) is 17%-73%. In cancer patients receiving 10 mg of this product once daily, the measured plasma concentration of everolimus was approximately 20% of the whole blood concentration. Plasma protein binding was approximately 74% in both healthy subjects and patients with moderate hepatic impairment.

(3) Metabolism

Everolimus is a CYP3A4 and PgP substrate. After oral administration, the main component in human blood circulation is everolimus.

Six major metabolites of everolimus have been detected in human blood, including 3 monohydroxylated metabolites, 2 hydrolysis products and 1 everolimus phosphatidylcholine conjugated compound. These metabolites have also been found in animal species used in toxicological studies and have been shown to be approximately 100 times less active than everolimus.

In in vitro experiments, everolimus competitively inhibits the metabolic activity of CYP3A4 and is a mixed inhibitor of the CYP2D6 substrate dextromethorphan. After oral administration of 10 mg/day once, the average steady-state Cmx is more than 12 times lower than the in vitro inhibition Ki value. Therefore, everolimus is unlikely to affect the metabolism of CYP3A4 and CYP2D6 substrates.

(4) Excretion

No specific excretion studies have been conducted in cancer patients. After a single oral dose of 3 mg of radiolabeled everolimus in transplant patients receiving cyclosporine, 80% of the radioactive material was excreted in the feces and 5% in the urine. The parent drug was not detected in urine or feces. The average elimination half-life of everolimus is approximately 30 hours.

(5) Steady-state pharmacokinetics

After daily or weekly administration of everolimus in patients with advanced solid tumors, the steady-state AUC0-τ is proportional to the dose within the daily dosing range of 5 to 10 mg and the weekly dosing range of 5 to 70 mg. Steady state is reached within two weeks on a daily dosing regimen. Cmax is dose-proportional over the 5 mg to 10 mg dose range in daily and weekly dosing regimens. At dose levels of 20 mg/week and higher, Cmax increases less than dose proportionally. Wx is reached 1-2 hours after dosing. When daily dosing reaches steady state, there is a significant correlation between AUC0-τ and the pre-dose trough concentration. The average elimination half-life of everolimus is approximately 30 hours.

7. Clinical application of Afinitor

Everolimus is mainly used clinically to prevent rejection after kidney transplantation and heart transplantation. Its mechanism of action mainly includes immunosuppressive effect, anti-tumor effect, anti-viral effect, and vascular protective effect. It is often used in combination with other immunosuppressants such as cyclosporine to reduce toxicity.

Compared with sirolimus, everolimus has superior pharmacokinetics.

Everolimus was first developed by the Swiss company Novartis and is available in tablets and dispersible tablets. Trade name Certican. It was first launched in Sweden in 2003 and has fully occupied the European market in 2006.

In addition, in addition to renal cell carcinoma, everolimus is also being studied in neuroendocrine tumors, lymphomas, other cancers, and tuberous sclerosis, either as a single agent or in combination with existing cancer treatments. As an investigational drug, the safety and efficacy of everolimus have not been fully established in the oncology field and are now in the clinical trial phase, which is conducted under strict control and monitoring. These trials are designed to better understand the compound's potential benefits and corresponding risks. Due to the uncertainty of clinical trials, it is not yet guaranteed that everolimus can be commercially sold globally as a drug for oncology indications.

8. Storage of Afinitor

Storage below 30℃. Protect from light and moisture. Prevent children from accidentally taking it.