Imatibe

Imatib is an anticancer drug, a protein tyrosine kinase inhibitor.

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Indications Imatiba

Shown in such cases:

• chronic myeloid leukemia in adults: during blast crisis, acceleration period, and also during the chronic stage, if previous treatment using Interferonum alpha was ineffective;
• tumors in the gastrointestinal tract in adults (inoperable form or malignant metastatic stromal);
• chronic stage of chronic myeloid leukemia in children aged 3+ years, if a relapse of the pathology has begun after stem cell transplantation, or if previous treatment with Interferonum alpha has not yielded results.

Release form

It is produced in capsules, 10 pieces per blister (3 blister blasts per pack), or 30 capsules in bottles (1 bottle per pack).

Pharmacodynamics

Imatinib is an antitumor agent that actively inhibits protein tyrosine kinase at the cellular level when tested in vitro and in vivo. The substance selectively inhibits proliferation and simultaneously stimulates the apoptosis process within positive Bcr-Abl cell lines and within cells recently affected by leukemia (patients who have the Philadelphia chromosome inside their leukocytes) in chronic positive myeloid leukemia, as well as in the acute stage of lymphoid leukemia.

Imatinib also effectively slows down tyrosine kinase receptors in stem cell and platelet growth factors, and also inhibits the cellular response provoked by the above factors. In vitro tests, the substance inhibits the proliferation process and promotes apoptosis inside stromal tumor cells in the gastrointestinal tract - this looks like activation of the kit mutation process.

Pharmacokinetics

Imatinib is rapidly absorbed after oral administration. The bioavailability index reaches approximately 98%. The substance reaches its peak level 2-4 hours after the drug is used. Synthesis with protein (usually albumin, as well as orosomucoid, and together with them, to a small extent, lipoprotein) is approximately 95%.

Over the dosage range of 25-1000 mg, the AUC level increases in proportion to the increase in dose size.

Metabolism occurs in the liver using the CYP3A4 enzyme of the P450 hemoprotein system. As a result, an active degradation product is formed - N-demethylated piperazine derivative, which has similar medicinal activity to imatinib in vitro.

The half-life of the active ingredient is approximately 18 hours. It is excreted mainly in the form of decay products: 68% in feces and 13% in urine. Approximately 25% of the substance is excreted unchanged.

Dosing and administration

When eliminating the chronic form of myeloid leukemia, the dosage of the drug will depend on the stage of the pathology. When treating the chronic stage, it is necessary to take 400 mg of the drug per day; during the acceleration period or blast crisis, the daily dose is 600 mg. The drug is taken once a day, with food, the capsule should be washed down with water (a full glass). The course of therapy is quite long, it is necessary to achieve and subsequently maintain hematological and drug remission.

If there are no adverse reactions, and also pronounced thrombocyto- or neutropenia (which are not associated with the underlying disease), under the following conditions it is allowed to increase the dosage of the drug: if the pathology progresses (at any time); if there is no hematological reaction after more than a 3-month course of therapy; if the previously achieved hematological reaction has been lost.

People with a chronic stage of the pathology are allowed to increase the daily dosage to 600 mg. During the blast crisis or acceleration stage, the daily dosage is allowed to be increased to 800 mg (divided into 2 doses - 400 mg).

During the treatment period, the selected dosage may need to be adjusted (this depends on the dynamics of changes in the blood platelet and neutrophil indices). If the patient develops thrombocyto- or neutropenia, the drug should be discontinued for a while or its dosage should be reduced (the choice of option depends on the severity of the side effects).

During treatment of the chronic stage of chronic myeloid leukemia (with an initial daily dosage of 400 mg), if the neutrophil level has decreased to less than 1.0x109/l, and the platelet level has decreased to less than 50x109/l, the drug must be discontinued. Treatment cannot be resumed until the neutrophil level exceeds 1.5x109/l, and the platelet level exceeds 75x109/l. Under these conditions, therapy can be continued (the daily dosage of the drug is 400 mg). If the platelet or neutrophil levels decrease again, the drug must be discontinued again, wait until the required level of indicators is restored, and then resume treatment using a daily dosage of 300 mg.

If at the acceleration or blast crisis stages (with an initial daily dose of 600 mg) the neutrophil counts fall below 0.5x109/l and the platelet count drops to less than 10x109/l, and this occurs after at least 1 month of treatment with Imatib, it is necessary to clarify whether cytopenia is developing due to leukemia (bone marrow biopsy or aspiration). If the above-mentioned connection is absent, it is necessary to reduce the daily dosage of the drug to 400 mg. If cytopenia continues over the next 2 weeks, it is necessary to reduce the daily dosage to 300 mg. If cytopenia continues to develop over the next 4 weeks (with an unconfirmed connection with leukemia), the drug should be discontinued until the neutrophil level exceeds 1x109/l and the platelet level exceeds 20x109/l. Therapy should be resumed with a daily dosage of 300 mg.

For malignant metastatic tumors (stromal) in the gastrointestinal tract, the daily dosage is 400-600 mg.

For children, the daily dose is 400 or 600 mg, which must be taken in one dose or twice (in the morning and in the evening).

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Use Imatiba during pregnancy

The drug is not prescribed to pregnant and lactating women.

Contraindications

Contraindications include: intolerance to imatinib. It should also not be prescribed to children under 3 years of age, as there is no information on the safety and effectiveness of the drug in the above-described category of patients.

Side effects Imatiba

As a result of using capsules, the following side effects may occur:

• hematopoiesis and hemostasis: slowing down of the hematopoietic process in the bone marrow area (development of thrombocyto, neutro-, pancyto or leukopenia, as well as anemia);
• nervous system organs: dizziness with headaches, development of paresthesia, polyneuropathy, muscle cramps, and also sleep disorders;
• cardiovascular system: dyspnea appears sporadically, blood pressure increases/decreases, pulmonary edema or tachycardia develops;
• Gastrointestinal tract: vomiting, constipation, nausea, diarrhea, development of anorexia; gastritis, ascites, tarry stools, and gastric ulcers occur sporadically;
• skin: baldness (reversible), damage to the nail plates and skin, development of peripheral edema;
• musculoskeletal system: occurrence of pain in muscles or joints;
• visual organs: the appearance of conjunctivitis, occasionally dryness of the mucous membranes of the eye, hemorrhage into the conjunctiva, periorbital edema, and also diplopia;
• allergic reactions: itching and skin rash;
• others: weakened resistance to infections of various origins, nosebleeds, and the development of pleural effusion;
• tests: increased activity of liver transaminases, as well as alkaline phosphatase, development of hyperbilirubinemia; in rare situations, hypokalemia, hypophosphatemia and hyperuricemia develop, and in addition, the level of uric acid increases; hyponatremia or hyperkalemia occur sporadically.

Interactions with other drugs

Inhibitors of the CYP3A4 enzyme (such as itraconazole with ketoconazole, as well as clarithromycin with erythromycin) increase the plasma level of imatinib. It is prohibited to combine the drug with paracetamol.

Imatinib increases the levels of CYP3A4 enzyme substrates (such as pimozide, cyclosporine or simvastatin), as well as elements of CYP2C9 (warfarin) and CYP2D6. In addition, drugs that are metabolized by CYP3A4 enzymes (including Ca channel blockers (included in the dihydropyridine category), triazolo-benzodiazepines, and HMG-CoA reductase inhibitors).

Inducers of the CYP3A4 enzyme (such as phenytoin with dexamethasone, phenobarbital, and rifampicin with carbamazepine) decrease serum levels of imatinib.

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Storage conditions

It is recommended to store the medicine in a dark, dry place, out of reach of children. Temperature – maximum 25°C.

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Shelf life

Imatib is approved for use for 2 years from the date of release of the drug.