$392.00
Manufacturer: Germany
Treatment of patients with advanced colorectal cancer: in combination with 5-fluorouracil and folic acid, when previous chemotherapy for the treatment of a common disease was not used; as monotherapy, when the established treatment regimen using 5-fluorouracil was ineffective. In combination with cetuximab, Irinotecan is used to treat metastatic colorectal cancer with a wild type of KRAS gene that expresses receptors for epidermal growth factor in patients who have not previously received treatment for metastatic cancer or for whom cytotoxic treatment with irinotecan has proved ineffective. In combination with 5-fluorouracil, folinic acid and bevacizumab, Irinotecan is used as a first-line therapy for patients with metastatic carcinomas of the colon or rectum.
Description
Irinotecan Amaxa Storage
active substance: irinotecan;
1 ml of concentrate contains 20 mg of irinotecan hydrochloride trihydrate, which corresponds to 17.33 mg of irinotecan;
Excipients: D-sorbitol, lactic acid, sodium hydroxide, water for injections.
Dosage form. Concentrate for solution for infusion.
Main physical and chemical properties: clear yellow solution.
Pharmacotherapeutic group. Other antineoplastic agents. Code ATX L01X X19.
Irinotecan Amaxa Pharmacological properties.
Pharmacodynamics.
Irinotecan Amaxa is a semi-synthetic substance derived from camptothecin. It is an antitumor drug that acts as a specific inhibitor of DNA topoisomerase I. Under the action of carboxylesterase in most tissues, the drug is metabolized to the compound SN-38, which in comparison with irinotecan is more active against purified topoisomerase I and more cytotoxic to a number of human tumor cell lines. . Inhibition of DNA topoisomerase I by irinotecan or SN-38 leads to damage to single-stranded DNA, which blocks the replicative plug of DNA and leads to cytotoxic effects. This cytotoxic effect was found to be time-dependent and specific for the S-phase of the cell cycle.
Patients with reduced UGT1A1 activity.
Uridine diphosphate-glucuronyltransferase 1A1 (UGT1A1) is involved in the metabolic inactivation of SN-38, the active metabolite of irinotecan, with the formation of inactive SN-38-glucuronide (SN-38G). The UGT1A1 gene is characterized by high polymorphism, which ensures the presence of various variants of metabolic intensity in the group. 1 special variant of the UGT1A1 gene contains a polymorphic region in the promoter region; this variant is called UGT1A1 * 28. This variant, as well as other inherited disorders of UGT1A1 expression (such as Gilbert’s syndrome or Kriegler-Nayar syndrome), have been associated with decreased activity of this enzyme. The results of the meta-analysis indicate that patients with Kriegler-Nayar syndrome (types 1 and 2) or homozygotes for the UGT1A1 * 28 allele (Gilbert’s syndrome) are at increased risk of hematological toxicity (grade III and IV) after administration of medium or high doses of irinotecan ( > 150 mg / m2). An association between the UGT1A1 genotype and the onset of diarrhea due to irinotecan has not been established.
Patients who are known to be homozygous for the UGT1A1 * 28 allele should use the usual starting dose of irinotecan. At the same time, such patients should be monitored for hematological toxicity. For patients who have already experienced haematological toxicity during previous courses of treatment, a reduction in the initial dose of irinotecan should be considered. The exact amount of reduction of the initial dose for this group of patients was not established. Any further dosage changes should be made based on how the patient tolerates the treatment (see sections “Method and Dosage” and “Specifics”). To date, there is insufficient clinical data to conclude on the feasibility of genotyping patients with UGT1A1 alleles.
Pharmacokinetics.
After administration of irinotecan at a dose of 100–750 mg / m2 by 30-minute intravenous infusion every two weeks, two- or three-phase plasma elimination of irinotecan is observed. The mean plasma clearance is 15 l / h / m2, the equilibrium volume of distribution (Vdss) is 157 l / m2 of body surface area. The mean plasma half-life during the first phase of the three-phase model was 12 minutes, during the second phase – 2.5 hours, during the third phase – 14.2 hours. Plasma elimination of SN-38 was biphasic with a mean terminal half-life of 13.8 hours.
Plasma protein binding is approximately 30-68% for irinotecan and 95% for the metabolite SN-38.
More than 50% of an intravenous dose of irinotecan is excreted unchanged, 33% is excreted in the faeces, mainly via bile, and 22% in the urine.
The clearance of irinotecan is reduced by almost 40% in patients with bilirubinemia (the concentration of total bilirubin in the serum is 1.5-3 times higher than the upper limit of normal). In these patients, a dose of 200 mg / m2 of irinotecan results in plasma exposure comparable to that of 350 mg / m2 in cancer patients with normal liver function.
The intensity of the most pronounced toxic effects of irinotecan (eg leukoneutropenia and diarrhea) is related to the effect (area under the concentration-time curve) of unchanged irinotecan and its metabolite SN-38. There was a significant relationship between haematological toxicity (reduction of white blood cells and neutrophils to a minimum) or the intensity of diarrhea and the area under the concentration-time curve of irinotecan and its metabolite SN-38 in monotherapy.
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