Irinotecan

Irinotecan has a cytostatic and antitumor drug effect. The drug specifically slows down the activity of topoisomerase I, exerting an effect mainly during the S-stage of the cell cycle.

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

Indications Irinotecan

It is used in the treatment of metastatic or locally advanced forms of rectal and colon carcinoma: in combination with Ca folinate and fluorouracil in persons who have not previously received chemotherapy.

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

Release form

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

Pharmacodynamics

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

In vitro cytotoxicity testing revealed that SN-38 is more active than irinotecan (2-2000 times). In this case, the AUC value for the SN-38 metabolite is within 2-8% of the same level 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 lactation form, and also exist in the inactive form of a hydroxy acid anion. Both of these forms are in an acidity-dependent equilibrium (an increase in pH promotes the formation of lactone, while an alkaline medium becomes a factor in the formation of a hydroxy acid anion). [3]

Pharmacokinetics

With intravenous infusion, the value of plasma elimination of irinotecan is multi-exponential; the half-life in the terminal stage is within 6-12 hours. SN-38 has a terminal half-life of 10-20 hours.

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

The drug metabolism processes mainly take place inside the liver under the influence of the carboxylesterase enzyme with the formation of SN-38. This metabolite is further involved in conjugation to form glucuronide, which is not as active. The level of glucuronide activity of the SN-38 element was 1 / 50–1 / 100 of the SN-38 values during in vitro cytotoxic tests using 2 cell lines.

Excretion through the kidneys 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 period of 48 hours after use in 2 patients was approximately 25% (0.1 g / m2) and 50% (0.3 g / m2).

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

Dosing and administration

The medicine must be administered through an intravenous infusion, which lasts within 0.5-1.5 hours. For the selection of a personal regimen of use and dosage size, it is necessary to use special literature.

In monotherapy, the serving size of Irinotecan is 0.125 g / m2, every week for a period of 1 month in the form of a 1.5-hour intravenous infusion at 2-week intervals. A dosage of 0.35 g / m2 may also be used at 3-week intervals, in the form of a 60-minute IV infusion.

In case of complex chemotherapy, together with Ca folinate and fluorouracil, the dosage of the drug for every week is 0.125 g / m2. For continuous infusion, 1 time at 2 week intervals, the serving size 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 forbidden to prescribe Irinotecan during breastfeeding and pregnancy.

Contraindications

Among the contraindications:

• severe intolerance to irinotecan;
• inflammation in the intestinal region, which is chronic in nature, or intestinal blockage;
• strong suppression of hematopoietic processes inside the bone marrow;
• serum bilirubin, which is more than three times higher than ULN;
• the patient's health status, according to the ECOG rating is> 2;
• use together with amarillosis vaccine.

Side effects Irinotecan

The main side symptoms:

• problems with hematopoietic function: often there is leuko-, neutro- or thrombocytopenia and anemia. In addition, there are reports of the development of thromboembolic complications in the veins and arteries (among them myocardial infarction, thrombosis (also arterial), angina pectoris, ischemia of the heart muscle, thrombophlebitis (also DVT of the legs) and stroke; circulatory disorders inside the brain or peripheral vessels are also possible, PE or thromboembolism of the vessels of the legs, sudden death, cardiac arrest and vascular disorders);
• disturbances in the gastrointestinal tract: diarrhea, anorexia, nausea, hiccups, abdominal pain, mucositis, vomiting, constipation and candidiasis in the gastrointestinal tract. Occasionally, intestinal obstruction, intestinal perforation, pseudomembranous-type colitis, bleeding inside the gastrointestinal tract, an increase in lipase or amylase activity were observed. Diarrhea that develops more than 24 hours after using the medication (delayed) is its dose-limiting toxic symptom;
• disorders of the NA activity: convulsions or twitching of muscles of an involuntary nature, asthenia, cephalalgia, paresthesia, confusion and gait disorder;
• lesions in the respiratory organs: infiltrates inside the lungs, dyspnea and runny nose;
• signs of allergy: occasionally epidermal symptoms, rashes, anaphylactoid manifestations and anaphylaxis appear;
• others: fever, local symptoms, alopecia, transient speech disorder, and dehydration. In addition, a temporary increase in the activity of alkaline phosphatase, transaminases and GGT, creatinine, bilirubin and serum urea nitrogen develops, pain, sepsis, hyponatremia, -volemia, -kalemia or -magnesaemia, disturbances in the work of the CVS, weight loss and fainting. Pain in the sternum, infection of the urogenital system, and tumor breakdown syndrome may also occur. Rarely, acute renal failure and renal dysfunction, insufficient blood flow or hypotension occur in people who have experienced dehydration caused by vomiting or diarrhea, or in people with sepsis.

Overdose

In case of overdose, diarrhea and neutropenia may appear.

Hospitalization is required, symptomatic measures and careful observation of the work of vital body systems. The drug has no antidote.

Interactions with other drugs

Since the drug has an anticholinesterase effect, when used together with suxamethonium salts, neuromuscular blockade can be prolonged; in the case of use in combination with non-depolarizing type muscle relaxants, an antagonistic effect regarding neuromuscular blockade may develop.

The use in combination with radiation therapy and myelosuppressants increases the toxic effect on the bone marrow (thrombocytosis, leukopenia).

The combination of drugs with corticosteroids (for example, dexamethasone) increases the likelihood of hyperglycemia (especially in diabetics or people with low glucose tolerance) and lymphocytopenia.

The introduction together with diuretics increases dehydration, which develops due to vomiting and diarrhea. The use of laxatives in combination with irinotecan may increase the severity and frequency of diarrhea.

The use in combination with prochlorperazine increases the risk of symptoms of akathisia.

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

The drug and its active metabolite SN-38 are involved in metabolic processes using the isoenzyme CYP3A4 and UDP-GT1A1. The introduction of drugs with substances that slow down the action of the isoenzyme CYP3A4 or UDP-HT1A1 can provoke an increase in the total exposure of the active substance and the decomposition product of SN-38. This point must be taken into account when using a combination of such drugs.

Administration simultaneously with atazanavir, ketoconazole, and in addition with drugs that inhibit CYP3A and UGT1A1 isoenzymes, can lead to an increase in the plasma index of the SN-38 degradation product.

The medicine cannot be mixed with other medicines inside the same bottle.

The use of an attenuated or live vaccine in people who are treated with anticancer drugs (among them Irinotecan) can provoke severe or fatal infections. It is necessary to refuse to administer a live vaccine to persons using irinotecan. An inactivated or killed vaccine can be administered, but the response to it may be weakened.

The combination of a medication with bevacizumab can lead to a mutual increase in toxic effects.

Storage conditions

Irinotecan should be stored at temperatures not exceeding 25 ° C. At a temperature within the 15-25 ° C mark, the medicine can be contained for no more than 24 hours, and in the case of dilution with 5% dextrose - at a temperature within 2-8 ° C, within 48 hours.

Shelf life

Irinotecan can be used for a 24-month term from the moment the therapeutic substance is marketed.