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Imatib
Imatib is an antitumor drug, an inhibitor of protein tyrosine kinase.
Indications of the imatiba
It is shown in such cases:
- the chronic form of myeloid leukemia in adults: with blast crisis, acceleration period, and also in chronic stage, if previous treatment with Interferonum alpha was ineffective;
- tumors in the digestive tract in adults (inoperable form or malignant metastatic stromal);
- a chronic stage of the chronic form of myeloid leukemia in children aged 3+ years, if a relapse of the pathology after stem cell transplantation has begun, or if the previous Interferonum alpha treatment did not work.
Pharmacodynamics
Imatinib is an antitumor agent, it actively slows down protein kinase at cell levels when tested in vitro, and also in vivo. The substance selectively inhibits proliferation and, at the same time, stimulates the process of apoptosis within the positive Bcr-Abl cell lines and inside cells recently affected by leukemia (patients who have leukocytes inside the Philadelphia chromosome) in the chronic form of positive myeloid leukemia as well as the acute stage of leukemia of the lymphoid type.
Also imatinib effectively slows down tyrosine kinase receptors in stem cell and platelet growth factors, and in addition inhibits the cellular response, which is provoked by the above factors. In in vitro tests, the substance inhibits the proliferation process and promotes apoptosis within the cells of the stromal tumor in the digestive tract - it looks like activation of the kit-mutation process.
Pharmacokinetics
Imatinib is absorbed with high speed after oral administration. The bioavailability index reaches about 98%. The peak level of the substance reaches 2-4 hours after the use of drugs. Synthesis with protein (this is usually albumin, as well as orosomukoid, and with them, to a small extent, lipoprotein) is approximately 95%.
At a dosage range of 25-1000 mg, the AUC level rises in accordance with the increase in the dose size.
Metabolism occurs in the liver using the enzyme CYP3A4 of the hemoprotein system P450. As a result, an active decay product is formed-an N-demethylated piperazine derivative, which has a drug activity similar to imatinib in vitro.
The half-life of the active ingredient is approximately 18 hours. Excreted mainly in the form of decomposition products: together with feces 68%, and with urine - 13%. Approximately 25% of the substance is excreted unchanged.
Side effects of the imatiba
Due to the use of capsules, there may be such side effects:
- hematopoiesis and hemostasis: slowing the hematopoietic process in the medullar region (development of thrombocytes, neutrophils, pancitos or leukopenia, and in addition anemia);
- organs of the National Assembly: dizziness with headaches, development of paresthesia, polyneuropathy, muscle cramps, and in addition, sleep disorder;
- organs of the cardiovascular system: dyspnea appears sporadically, the level of blood pressure rises / falls, pulmonary edema or tachycardia develops;
- organs of the digestive tract: the emergence of vomiting, constipation, nausea, diarrhea, the development of anorexia; there is a single gastritis, ascites, tarry stool, and gastric ulcer;
- skin: alopecia (reversible), lesion of nail plates and skin, development of peripheral edemas;
- organs ODA: the occurrence of pain in the muscles or joints;
- visual organs: the appearance of conjunctivitis, the dryness of the eye mucous membranes, hemorrhage into the conjunctiva, periorbital puffiness, and, in addition, diplopia;
- allergic manifestations: itching and skin rash;
- other: weakening resistance to infections of various genesis, nosebleeds, as well as the development of pleural effusion;
- Analyzes: an increase in the activity of liver transaminases, as well as alkaline phosphatase, the development of hyperbilirubinemia; in rare situations develops hypokalemia, hypophosphatemia and hyperuricemia, and in addition, the level of uric acid increases; there are hyponatremia or hyperkalemia.
Dosing and administration
When eliminating the chronic form of myeloid leukemia, the dosage of the drug will depend on the stage of pathology. In the treatment of chronic stage, 400 mg of medicine per day is required; at the time of acceleration or blast crisis, the daily dose is 600 mg. For a day, the medicine is used once, along with the food, the capsule should be filled with water (a full glass). The course of therapy is rather long, it is necessary to achieve and further support hematological and remission remission.
If there are no negative reactions, and in addition expressed thrombocytopathic or neutropenia (which are not associated with the underlying disease), under the following conditions it is permitted to increase the dosage of drugs: if the pathology progresses (at any time); if there is no hematologic response after more than 3 months of therapy; if the previously hematologic reaction was lost.
People with a chronic stage of pathology are allowed to increase the daily dosage to 600 mg. During the blast crisis or the stage of acceleration, it is allowed to increase the daily dose to 800 mg (divided by 2 administration - 400 mg).
During the treatment period, sometimes a correction of the chosen dosage is required (this depends on the dynamics of changes in the blood of platelet counts with neutrophils). If the patient develops thrombocytopenia or neutropenia, it is necessary to cancel the drug for a while or to lower its dosage (the choice of option depends on the severity of the side effects).
During the treatment of the chronic stage of the chronic form of myeloid leukemia (with an initial daily dosage of 400 mg), if the neutrophil count drops to less than 1.0x109 / l, and the platelet count drops to less than 50x109 / l, drug withdrawal is required. Renewal of treatment is impossible until the neutrophil count does not exceed 1.5x109 / l, and platelets - the figure of 75x109 / l. Under these conditions, it is allowed to continue therapy (daily dosage of LS is 400 mg). If the platelet count or neutrophil counts decrease again, the drug should be canceled again, wait for the recovery of the required level of indicators, and then resume treatment with a daily dosage of 300 mg.
If at the stages of acceleration or blast crisis (with an initial daily dose of 600 mg) the neutrophil count falls below 0.5x109 / l, and the platelet count drops to less than 10x109 / l, and this occurs after a minimum of 1 month of treatment with Imatib, It is required to clarify whether cytopenia develops because of leukemia (bone marrow biopsy or aspiration). In the absence of the above-mentioned connection, it is necessary to reduce the daily dosage of LS to 400 mg. If cytopenia continues for the next 2 weeks, the daily dosage should be reduced to 300 mg. With continued development of cytopenia during the next 4 weeks (with unconfirmed association with leukemia), it is required to cancel the drug until the neutrophil level exceeds 1x109 / l, and the platelet count does not exceed 20x109 / l. Renewal therapy should be taken with a daily dosage of 300 mg.
In 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 1 session or twice (in the morning, and also in the evening).
Interactions with other drugs
Inhibitors of the enzyme CYP3A4 (such as itraconazole with ketoconazole, as well as clarithromycin with erythromycin) increase the plasma level of imatinib. It is forbidden to combine the drug with paracetamol.
Imatinib increases the substrates of CYP3A4 enzymes (such as pimozide, cyclosporine or simvastin), as well as elements of CYP2C9 (this is warfarin) and CYP2D6. In addition, also drugs that are metabolized by enzymes CYP3A4 (among them are blockers of the Ca channels (included in the dihydropyridine category), triazolo benzodiazepines, and with it HMG-CoA reductase inhibitors).
Inductors of the CYP3A4 enzyme (such as phenytoin with dexamethasone, phenobarbital and rifampicin with carbamazepine) reduce the serum level of imatinib.