Irinotecan

Irinotecan has cytostatic and antitumor medicinal effects. The drug specifically inhibits the activity of topoisomerase I, acting mainly during the S-stage of the cell cycle.

The drug is a precursor of the lipophilic breakdown product SN-38 (water-soluble type). The element SN-38 is approximately 1000 times more potent than irinotecan, it inhibits the activity of topoisomerase I secreted by tumor cell lines in rodents or humans. [ 1 ]

Indications Irinotecan

It is used in the treatment of metastatic or locally advanced forms of carcinoma of the rectum and colon: in combination with calcium folinate and fluorouracil in individuals who have not previously undergone chemotherapy.

It is prescribed as monotherapy for people with progression of pathology after standard antitumor treatment procedures.

Release form

The medicinal substance is released in the form of a concentrate for infusion fluid (0.04, 0.1 and 0.3 g) - inside a 2 ml bottle. There is 1 such bottle inside the pack.

Pharmacodynamics

The drug is involved in metabolic processes with the formation of the active metabolic product SN-38, which is more powerful than irinotecan. These components normalize the connection of DNA and topoisomerase I, thereby preventing replication. Irinotecan has an anticholinesterase effect.

In vitro cytotoxicity testing has shown that SN-38 is more active than irinotecan (2-2000 times). The AUC value for the SN-38 metabolite is within 2-8% of that of irinotecan; protein synthesis (mainly with albumin) is 95% for SN-38, compared to 30-68% for irinotecan. Because of this, it is impossible to determine the exact contribution of the SN-38 element to systemic drug exposure. [ 2 ]

Both components have an active lactone form and also exist in an inactive hydroxyacid anion form. Both of these forms exist in an acidity-dependent equilibrium (increasing pH promotes the formation of lactone, while an alkaline environment becomes a factor in the formation of hydroxyacid anion). [ 3 ]

Pharmacokinetics

When administered intravenously, the plasma elimination rate of irinotecan is multiexponential; the terminal half-life is 6-12 hours. For SN-38, the terminal half-life is 10-20 hours.

When using doses of 0.05-0.35 g/m2, the AUC value of irinotecan increases linearly; the AUC value of SN-38 does not increase proportionally with increasing dosage. The plasma level of Cmax of the SN-38 component is often observed in the period of 1 hour after completion of a 1.5-hour infusion of the drug.

The metabolism of the drug occurs mainly in the liver under the influence of the enzyme carboxylesterase with the formation of SN-38. This metabolite is then involved in conjugation with the formation of a glucuronide, which is not as active. The activity level of the glucuronide of the SN-38 element was 1/50–1/100 of the SN-38 values during in vitro cytotoxicity testing using 2 cell lines.

Renal excretion is 11-20% for unchanged irinotecan, less than 1% for SN-38, and 3% for SN-38 glucuronide. Systemic biliary and renal excretion of the drug over a 48-hour period after administration in 2 patients was approximately 25% (0.1 g/m2) and 50% (0.3 g/m2).

The Vd value at the terminal stage of excretion of irinotecan is 110 l/m2. The overall clearance values of irinotecan are 13.3 l/h/m2.

Dosing and administration

The medicine should be administered via intravenous infusion, which lasts within 0.5-1.5 hours. To select a personal regimen and dosage, it is necessary to use special literature.

For monotherapy, the dose size of Irinotecan is 0.125 g/m2, every week for the first month as a 1.5-hour intravenous infusion at 2-week intervals. A dose of 0.35 g/m2 can also be used at 3-week intervals, as a 60-minute intravenous infusion.

In combination chemotherapy with calcium folinate and fluorouracil, the dosage of the drug for weekly use is 0.125 g/m2. For long-term infusion once at 2-week intervals, the dose is 0.18 g/m2.

• Application for children

Not used in pediatrics (there is no information on the therapeutic efficacy and safety of the drug in this category).

Use Irinotecan during pregnancy

It is prohibited to prescribe Irinotecan during breastfeeding and pregnancy.

Contraindications

Among the contraindications:

• severe intolerance to irinotecan;
• inflammation in the intestinal area, which is chronic in nature, or intestinal obstruction;
• strong suppression of hematopoietic processes within the bone marrow;
• serum bilirubin level that is more than three times the ULN;
• the patient's health status, according to the ECOG rating, is >2;
• use in conjunction with amaryllosis vaccine.

Side effects Irinotecan

Main side effects:

• problems with hematopoietic function: leukopenia, neutro- or thrombocytopenia and anemia often occur. In addition, there are reports of thromboembolic complications in the veins and arteries (including myocardial infarction, thrombosis (also arterial), angina pectoris, myocardial ischemia, thrombophlebitis (also DVT of the legs) and stroke; circulatory disorders within the brain or peripheral vessels, pulmonary embolism or thromboembolism of the leg vessels, sudden death, cardiac arrest and vascular disorders are also possible);
• gastrointestinal disorders: diarrhea, anorexia, nausea, hiccups, abdominal pain, mucositis, vomiting, constipation and candidiasis in the gastrointestinal tract. Intestinal obstruction, intestinal perforation, pseudomembranous colitis, intragastrointestinal bleeding, increased lipase or amylase activity were rarely observed. Diarrhea that develops more than 24 hours after using the drug (delayed) is its dose-limiting toxic symptom;
• disorders of the nervous system: involuntary muscle cramps or twitching, asthenia, cephalgia, paresthesia, confusion and gait disturbance;
• lesions in the respiratory system: infiltrates inside the lungs, dyspnea and runny nose;
• signs of allergy: epidermal symptoms, rashes, anaphylactoid manifestations and anaphylaxis occasionally appear;
• Others: fever, local symptoms, alopecia, transient speech disorder, and dehydration. In addition, transient increases in alkaline phosphatase, transaminase, and GGT levels, creatinine, bilirubin, and serum urea nitrogen, pain, sepsis, hyponatremia, -volemia, -kalemia, or -magnesemia, cardiovascular dysfunction, weight loss, and syncope may occur. Chest pain, urogenital infections, and tumor lysis syndrome may also occur. Rarely, acute renal failure and renal dysfunction, poor blood flow, or hypotension may occur in people who have experienced dehydration due to vomiting or diarrhea, or in people with sepsis.

Overdose

In case of overdose, diarrhea and neutropenia may occur.

Hospitalization, symptomatic measures and careful monitoring of vital body systems are required. The drug has no antidote.

Interactions with other drugs

Since the drug has an anticholinesterase effect, when used together with suxamethonium salts, neuromuscular blockade may be prolonged; when used in combination with non-depolarizing muscle relaxants, an antagonistic effect relative to neuromuscular blockade may develop.

Use in combination with radiation therapy and myelosuppressants increases the toxic effect on the bone marrow (thrombocytopenia, leukopenia).

Combining the drug with GCS (for example, dexamethasone) increases the likelihood of hyperglycemia (especially in diabetics or people with low glucose tolerance) and lymphopenia.

Administration with diuretics increases dehydration due to vomiting and diarrhea. Use of laxatives in combination with Irinotecan may increase the severity and frequency of diarrhea.

Use in combination with prochlorperazine increases the risk of developing akathisia symptoms.

Combination of the drug with herbal substances containing Hypericum perforatum, as well as with anticonvulsants that induce the CYP3A isoenzyme (such as phenobarbital, carbamazepine or phenytoin), causes a decrease in the plasma level of the active breakdown product SN-38.

The drug and its active metabolite SN-38 participate in metabolic processes with the help of the isoenzyme CYP3A4 and UDP-GT1A1. The introduction of drugs with substances that slow down the action of the isoenzyme CYP3A4 or UDP-GT1A1 may provoke an increase in the total exposure of the active substance and the breakdown product SN-38. This point should be taken into account when using a combination of such drugs.

Concomitant administration with atazanavir, ketoconazole, and also with drugs that inhibit CYP3A and UGT1A1 isoenzymes may lead to an increase in the plasma level of the SN-38 breakdown product.

The medicine must not be mixed with other medications in the same bottle.

Use of a weakened or live vaccine in people who are being treated with anticancer drugs (including Irinotecan) may cause severe or fatal infections. Live vaccines should be avoided in people taking Irinotecan. Inactivated or killed vaccines can be administered, but the response to them may be weakened.

The combination of the drug with bevacizumab may lead to a mutual increase in toxic effects.

Storage conditions

Irinotecan should be stored at temperatures no higher than 25°C. At a temperature of 15-25°C, the medicine can be stored for no more than 24 hours, and in the case of dilution with 5% dextrose - at a temperature of 2-8°C, for 48 hours.

Shelf life

Irinotecan can be used for a period of 24 months from the date of sale of the therapeutic substance.