Decitabine

When ATH:
L01B

Pharmacological action.

The antitumor agent, antimetaʙolit, natural nucleoside analogue 2′-deoxycytidine, It is an inhibitor of DNA methyltransferase enzyme. Methylation and demethylation is associated with the control of gene expression. Methylation of the promoter region of the gene or close to the site inhibits transcription of the. DNA demethylation restores expression of the gene. Gene activation detsitabinom, It can be expressed in the differentiation induction, the desired effect in the treatment of myelodysplastic syndromes, etc.. malignant tumors of blood, activation of tumor suppressor genes, etc.. Genov, whose effect extends to many types of tumors. Complexes of DNA methyltransferase enzyme and 5-aza-deoxycytidine could induce apoptosis, when the cell exits the cycle of DNA synthesis and cell cycle induced isolation and mitotic block. The result of the effects of decitabine can be overcome drug resistance, relief immune responses, Induction of apoptosis. Decitabine acts in the S-phase of the cell cycle. Cells alone should reach S-phase, to show maximum effect of decitabine.

Pharmacokinetics

When infusion 100 mg / m for 1 no, plasma concentration is increased during infusion, then decreases dwuhfazno; Cmax - 0,359-0,559 mg / ml, AUC - 320-496 ng x h / ml. Patients, receiving 72-hour infusion at a dose 20, 25 or 30 mg / m / day, AUC — 385–701, 645–841, 619-867 Ng x h / ml, respectively. The volume of distribution (при Css) - 3,17-6,01 l / kg. Contact proteins - less 1%. The main pathway - deamination of cytidine deaminase, present in the liver, in granulocytes, intestinal epithelium, plasma. In vitro studies suggest, decitabine that is not a substrate of cytochrome P450 enzymes of human liver. When infusion 100 mg / m for 1 h total clearance 104-147 mL / min / kg (exceeds the hepatic blood flow), that indicates the presence of extrahepatic metabolism decitabine . The final T1 / 2 - 30-40 minutes. Excreted in the urine primarily as metabolites, less 1% - Unchanged.

Testimony

Myelodysplastic syndrome all types.

Contraindications

Hypersensitivity, pregnancy, lactation.

Carefully.

Renal / hepatic impairment.

Batching

First cycle: I / continuous 15 mg / m for 3 every hour 8 h for 3 days (premedication with antiemetic drugs at standard doses).

Cycles through 6 Sun (minimum 4 Sun) may continue for as long, how therapeutic effect persists. Dose adjustment or postponement of the next injection is carried out on the results of the general analysis of blood.

If the recovery of hematological parameters (to 1000 neutrophils / ml or more, platelets to 50,000 / l and more) It requires more 6 weeks, then lay the next cycle, temporarily reduce the dose on the following algorithm: if the recovery requires 6-8 weeks, delaying the introduction of up to 2 Sun, reduce the dose 11 mg / m every 8 no (33 mg / m / day, of course - 99 mg / m); if the recovery requires 8-10 weeks, and in the case, If the disease does not progress (conducting a survey), delaying the introduction of a further 2 Sun; administered at a dose of 11 mg / m every 8 no (33 mg / m per day, of course - 99 mg / m).

In subsequent cycles the dose may be maintained or increased, depending on the clinical indications.

When the concentration of creatinine 177 mmol / l, indicator ALT and total bilirubin, exceeding in 2 times the upper limit of normal, acute infection, exacerbation of chronic infections, uncontrolled infection, resume treatment after their elimination.

Side effect

From the nervous system: headache, dizziness, giperesteziya, insomnia, confusion.

The respiratory system: cough, pharyngitis, wheezing in the lungs, gipoksiya.

From the side of hematopoiesis: neutropenia, thrombocytopenia, anemia, febrile neutropenia, leukopenia.

From the digestive system: nausea, constipation, diarrhea, vomiting, abdominal pain, rash on the mucous membrane of the mouth, stomatitis, dyspepsia, ascites.

On the part of the musculoskeletal system: arthralgia, pain in the extremities, lower back.

For the skin: ecchymosis, rash, эritema, skin lesion, unspecified, itch, petechiae, paleness.

Local reactions: soreness at the injection site.

Other: anorexia, fever, peripheral edema, tremor, edema, unspecified, pain, unspecified, lymphadenopathy, lethargy, pneumonia, cellulitis, Candidiasis, unspecified, herpes simplex.

Laboratory findings: giperglikemiâ, hypoalbuminemia, gipomagniemiya, kaliopenia, hyperkalemia, increase in blood urea.

Overdose.

Symptoms: severe myelosuppression, including delayed neutropenia, thrombocytopenia, giperkreatininemiю.

Treatment: symptomatic.

Drug Interactions

Decitabine is metabolized by cytidine deaminase, However, the ability to interact with others. enzyme substrates is small, tk. Rm (Michaelis constant) decitabine is relatively large (250 M). Relationship to plasma proteins less 1%, Therefore, the interaction, due to the displacement of drugs from protein binding sites, pitifully.

The called decitabine myelosuppression may be enhanced so. antitumor drugs.

Monotherapy tamoksifenom soprovozhdaetsya trombotsitopeniey (platelet count less than 100,000 / mm) and thromboembolic complications (aggravated by the simultaneous use of other. anticancer drugs). Should be weighed against the risks and benefits of the combined use of decitabine and tamoxifen. It is necessary to observe the patient to identify the symptoms of bleeding and thromboembolism.

Cautions.

Use of the drug associated with the development of neutropenia and thrombocytopenia, so for subsequent cycles of treatment should be to adjust the dose and time of the cycle. It is necessary to take into account the early use of growth factors and / or antimicrobial, antifungal, antiviral drugs for the treatment of presumed infection. Myelosuppression and increased neutropenia 1 and 2 the cycle is not necessarily indicative of the progression of myelodysplastic syndrome. Total blood count is performed at a frequency, necessary to monitor therapeutic and toxic effects (possible prior to each treatment cycle).

Before treatment assess liver function and creatinine concentration in blood.

During the treatment, and 2 Months after, men and women should use reliable contraception. In preclinical studies, a decrease of weight, violation of testicular histology, significant reduction of spermatozoa, reduction in the incidence of pregnancy loss and an increase in the frequency of a fertilized egg.

Women of reproductive age should refrain from pregnancy, the same applies to partners of men, treated. In the treatment during pregnancy, should inform the patient about the harm to the fetus.

Unknown, Whether or decitabine and its metabolites in breast milk (because of the potential for serious adverse effects in infants, should discuss the possibility of stopping breastfeeding, given the need to treat the mother).