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Pharmacological properties

imatinib is a protein tyrosine kinase inhibitor that strongly inhibits bcr-abl tyrosine kinase in vitro at the cellular and in vivo levels. this compound selectively suppresses proliferation and stimulates apoptosis in bcr-abl-positive cell lines, as well as in newly diseased leukemic cells in patients with the Philadelphia chromosome in leukocytes in chronic positive myeloid leukemia (ph +) and acute lymphoblastic leukemia (all).

In vivo, the compound exhibits antitumor activity during monotherapy in an animal model of Bcr-Abl-positive tumor cells. In addition, imatinib is a potent inhibitor of the tyrosine kinase receptor relative to platelet growth factor (TGF) and embryonic cell factor (FEC), c-Kit, and inhibits TGF and FEC-mediated changes in the cells. In vitro, imatinib inhibits proliferation and stimulates apoptosis in the cells of the gastrointestinal stromal tumor (GISO), which is expressed in the activation of the Kit mutation.

Constitutive activation of the TGF receptor or Bcr-Abl protein tyrosine kinase results from integration with various proteins or stimulation of TGF synthesis, which were involved in the pathogenesis of myelodysplastic syndrome (MDS) / myeloproliferative disease (MPD), hypereosinophilic syndrome (HES) / chronic eosinophilic leukemia and bulging dermatofibrosarcomas (DFSP). Imatinib inhibits the signal for the proliferation of cells accompanying deactivated TGF and the activity of Bcr-Abl tyrosine kinase.

The effectiveness of the drug is based on the usual hematological and cytogenetic data of the level of response to treatment and life expectancy without disease progression in chronic myeloid leukemia (CML), on the usual hematological and cytogenetic data of the level of response with Ph+ ALL, MDS / MPZ and on an objective response with GISO and inoperable DFSP.

Pharmacokinetics The effect of imatinib was studied when administered in a dose range of 25–1000 mg. Pharmacokinetic profiles were analyzed on the 1st day, as well as on the 7th or 28th day, when equilibrium plasma concentrations of imatinib were reached.

Suction. The average absolute bioavailability of the drug is 98%. The coefficient of variation for AUC of imatinib in blood plasma has different levels in patients with oral administration. When prescribing the drug with food with a high fat content compared with fasting, there is a slight decrease in the degree of absorption (decrease in Cmax imatinib by 11% and increased time to reach Cmax by 1.5 hours with a slight decrease in AUC (7.4%)). The effect of previous surgery on the digestive tract on the absorption of the drug has not been studied.

Distribution. According to in vitro studies, at clinically significant concentrations, about 95% of imatinib binds to plasma proteins (mainly with albumin and acidic α-glycoprotein, to a small extent with lipoprotein).

Metabolism. The main metabolite of imatinib, which circulates in the bloodstream, is the N-demethylated piperazine derivative, which exhibits an in vitro power similar to that of the starting material. The plasma AUC for this metabolite is only 16% AUC for imatinib. The binding to plasma proteins of an N-demethylated metabolite is similar to the binding of the parent compound.

Imatinib and the N-demethylated metabolite together account for about 65% of the circulating radioactivity (AUC0-48) The remainder of the circulating radioactivity is comprised of numerous minor metabolites.

According to in vitro studies, it was found that CYP 3A4 is the main human P450 enzyme that catalyzes the biotransformation of imatinib. Of the group of potential drugs for simultaneous treatment (acetaminophen, acyclovir, allopurinol, amphotericin, cytarabine, erythromycin, fluconazole, oxyurea, norfloxacin, penicillin V) only erythromycin (IC50 50 μm) and fluconazole (IC50 118 μm) showed an inhibitory effect on metabolism, metabolism which may have clinical significance.

Imatinib, according to in vitro studies, has shown that it can be a competitive inhibitor of the substrate marker CYP 2C9, CYP 2D6 and CYP 3A4 / 5. The value of competitive inhibition (Ki) in the microsomes of the human liver was 27; 7.5 and 7.9 μmol / L, respectively. Cmax Imatinib in the blood plasma of patients is 24 μmol / L, therefore, inhibition of CYP 2D6 and / or CYP 3A4 / 5 metabolism of simultaneously administered drugs is possible. Imatinib does not interfere with the biotransformation of 5-fluorouracil, but inhibits paclitaxel metabolism as a result of competitive inhibition of CYP 2C8 (Ki= 34.7 μm). Such a value of Ki significantly higher than the expected plasma concentration of imatinib in patients, therefore there is no reason to expect interaction with the simultaneous administration of 5-fluorouracil or paclitaxel with imatinib.

After oral administration 14About 81% of C-labeled imatinib is excreted over 7 days, with feces - 68% of the administered dose, with urine - 13% of the dose. About 25% of the dose is excreted unchanged (20% with feces and 5% with urine). The rest is excreted in the form of metabolites.

Plasma pharmacokinetics. T½ imatinib in healthy volunteers is about 18 hours, which is confirmed by the fact that the appointment of the drug 1 time per day is acceptable. In the dose range of 25–1000 mg, a direct linear dependence of AUC on the dose is observed. With the introduction of repeated doses, which are prescribed once a day, the pharmacokinetics of imatinib does not change, the cumulation of the drug with a constant dose of 1 time per day was 1.5–2.5 times the initial value.

Pharmacokinetics in patients with GISO. In patients with GISO, the exposure was 1.5 times greater than in patients with CML using the same dose (400 mg). Based on a preliminary analysis of the pharmacokinetics in patients with GISO, three variables (albumin, leukocytes and bilirubin) were established that were statistically related to the pharmacokinetics of imatinib. A decrease in albumin levels caused a decrease in clearance (CL / F), as well as a higher white blood cell count, which led to a decrease in CL / F. However, these indicators are not significant enough to adjust the dose. In this category of patients, the presence of metastases in the liver can potentially lead to liver failure and a decrease in metabolism.

Pharmacokinetics of populations. Based on pharmacokinetic data in patients with CML, a small effect of age on the volume of distribution was established (an increase of 12% in patients over the age of 65). This change cannot be considered clinically significant. A slight effect of body weight on the clearance of imatinib was noted; for patients with a body weight of 50 kg, the average clearance is 8.5 l / h, and for patients with a body weight of 100 kg this figure will increase to 11.8 l / h. These changes are not a sufficient basis for dose adjustment, which is determined depending on body weight. The pharmacokinetics of imatinib is also independent of gender.

Pharmacokinetics in children. As in adult patients, imatinib in children is rapidly absorbed after oral administration in both phases of the study. Use in children at doses of 260 and 340 mg / m2/ day reaches the same clinical value as doses of 400 and 600 mg in adult patients. AUC Comparison0-24 on the 8th day and on the 1st day at a dose level of 340 mg / m2/ day revealed a 1.7-fold accumulation after repeated administration 1 time per day.

Based on a generalized pharmacokinetic analysis of populations of children with hematological disorders (CML, Ph+ ALL or other hematologic disorders treated with imatinib), it was found that imatinib clearance increases with increasing body surface area. After correcting the influence of body surface area, other demographic factors, such as age, body weight, body mass index, do not have a clinically important effect on imatinib exposure. The analysis confirms that the exposure of imatinib in children taking a dose of 260 mg / m2 1 time per day (without exceeding the dose of 400 mg 1 time per day) or 340 mg / m2 (without exceeding a dose of 600 mg 1 time per day), it was similar to that in adult patients who took imatinib at a dose of 400 or 600 mg 1 time per day.

Patients with impaired organ function. Imatinib and its metabolites are excreted by the kidneys in a significant amount.Patients with mild to moderate impaired renal function have a higher plasma exposure than patients with normal renal function. The growth is about 1.5–2 times, which corresponds to a 1.5-fold increase in the level of alpha-glycoprotein in blood plasma, with which imatinib is largely associated. The clearance of the free drug imatinib is probably close in value in patients with renal failure and normal renal function, since renal excretion is considered a secondary route of excretion of imatinib.

Although the results of pharmacokinetic analysis showed significant interpersonal variability, the average exposure of imatinib was not increased in patients with impaired liver function of varying degrees compared with patients with normal liver function.

Indications

Treatment of patients (adults and children) with newly diagnosed positive (ph +) (with the presence in the leukocytes of the Philadelphia chromosome (bcr-abl)) CML, for which bone marrow transplantation is not considered as the first line of therapy;

treatment of patients (adults and children) with (Ph+ CML) in the chronic phase after an unsuccessful treatment with interferon alfa or in the acceleration phase or in the phase of the blast crisis of the disease;

as part of chemotherapy for patients (adults and children) with first diagnosed positive acute lymphoblastic leukemia (Ph+ ALL) with the presence in the leukocytes of the Philadelphia chromosome;

as monotherapy for adult patients with acute lymphoblastic leukemia (Ph+ ALL) in relapse or difficult to treat;

treatment of adult patients with MDS / MPZ associated with TGF receptor gene rearrangement;

treatment of adults with HES and / or HEL with FIP1L1 – PDGFRα gene remodeling;

treatment of adult patients with Kit (CD117) -positive inoperable and / or metastatic malignant GISO;

adjuvant therapy in adult patients who have a high risk of relapse of Kit (CD117) -positive malignant GISO after resection (patients who have a low or minimal risk may not receive adjuvant therapy);

treatment of adult patients with inoperable bulging DFSP and adult patients with recurrent and / or metastatic DFSP that cannot be removed surgically.

Application

Treatment is prescribed by a doctor who has experience in treating patients with malignant hematological diseases and malignant tumors.

The drug is taken orally during meals, washed down with plenty of water to minimize the risk of gastrointestinal complications. The drug in doses of 400-600 mg is used 1 time per day, while the drug in a daily dose of 800 mg should be used 400 mg 2 times a day, in the morning and in the evening.

For patients (including children) who cannot swallow the capsule, its contents can be dissolved in 1 glass of water or apple juice. Since there is evidence of reproductive toxicity of the drug and the potential risk to human fertility, women of reproductive age who open capsules should be careful to avoid contact of the drug with skin and mucous membranes. After opening the capsule, hands should be washed immediately.

Doses for CML for adult patients. The recommended dose for patients with CML in the chronic phase is 400 mg / day, in the blast crisis and acceleration phases - 600 mg / day.

The chronic phase of CML is differentiated according to the following criteria: blast forms of 15% in blood and bone marrow, basophils in peripheral blood 20%, platelets 100 · 109/ l

The acceleration phase is differentiated by the presence of one of the following indicators: blast forms ≥15%, but 30% in the blood and bone marrow, blasts and promyelocytes ≥30% in the blood or bone marrow (gives 30% blasts), basophils in peripheral blood ≥20 %, platelets 100 · 109/ l, which is not associated with treatment.

The blast crisis phase is differentiated by the presence of blasts ≥30% in the blood and bone marrow or the presence of non-bone marrow diseases, with the exception of hepatosplenomegaly.

Treatment should be continued until the clinical effect persists. The effect of discontinuing treatment after reaching a complete cytogenetic response has not been studied.

The question of increasing the dose from 400 to 600 mg for patients with the chronic phase of the disease and from 600 mg to a maximum of 800 mg (prescribed 400 mg 2 times a day) for patients with the disease in the acceleration phase or in the blast crisis phase can be considered provided that there is no severe adverse reactions and severe neutropenia and thrombocytopenia, not associated with the underlying disease, in such conditions: disease progression (at any stage); lack of sufficient hematological response after 3 months of treatment; loss of a previously achieved hematological and / or cytogenetic response or lack of a cytogenetic response to treatment after 12 months of therapy. Patients are subject to close monitoring after increasing the dose, since the incidence of adverse reactions at higher doses increases.

Doses for CML for children. Doses for children are determined in accordance with the surface area of ​​the body (mg / m2) For children with a chronic phase of CML and the acceleration phase, respectively, the recommended dose is 340 mg / m2/ day (dose should not exceed 800 mg). The drug can be prescribed 1 time per day or the daily dose can be divided into 2 doses - in the morning and in the evening. The recommended dose is based on studies conducted with a small number of pediatric patients. There is no experience in the use of the drug in children under the age of 2 years.

In the absence of serious adverse reactions in children and serious disorders associated with leukemia, neutropenia or thrombocytopenia, the dose can gradually be increased from 340 to 570 mg / m2/ day (dose should not exceed 800 mg) in such cases: disease progression (at any stage); lack of sufficient hematological response after 3 months of treatment; lack of a cytogenetic response to treatment after 12 months of therapy; loss of previously achieved hematological and / or cytogenetic response. Patients are subject to close monitoring after increasing the dose, since the incidence of adverse reactions at higher doses increases.

Doses at Ph+-ALL for adult patients. Recommended Dose for Patients with Ph+ALL is 600 mg / day. Patients are closely monitored in any phase of the disease.

Treatment regimen: the drug is effective and safe at a dose of 600 mg / day in combination with chemotherapy in the induction, consolidation phase, with maintenance chemotherapy for adult patients with Ph+-OLL. The duration of treatment may vary with the use of various treatment programs, but prolonged exposure had a more pronounced result.

In adult patients with relapsed disease or difficult to treat Ph+-ALL use the drug as monotherapy at a dose of 600 mg / day, which is safe and effective and can continue until disease progression is noted.

Doses for MDS / MPZ. The recommended dose for patients with MDS / MPZ is 400 mg / day. Duration of treatment: only one clinical trial has been completed so far; imatinib treatment continues until disease progression. At the time of the analysis, the median duration of treatment was 47 months (24 days – 60 months).

Doses at hydroelectric stations and HEL. The recommended dose for patients with HES / HEL is 100 mg / day.

Increasing the dose from 100 to 400 mg can be considered in patients who have not been identified adverse reactions, and if the response to treatment is not effective enough.

Treatment may continue as long as the patients condition improves.

Doses for malignant tumors of the stroma of the digestive tract. The recommended dose for patients with inoperable and / or metastatic malignant tumors of the stroma of the digestive tract is 400 mg / day.

The feasibility of increasing the dose from 400 to 600 or 800 mg / day can be considered in patients who have not identified adverse reactions, and if the response to treatment is not effective enough.

Duration of treatment: treatment of patients with malignant tumors of the stroma of the digestive tract should be continued while the disease progresses. The median duration of treatment is 7 months (from 7 days to 13 months). The effect of discontinuing treatment after reaching an answer has not been studied.

The recommended dose for adjuvant therapy of adult patients with GISO resection is 400 mg / day. The optimal duration of treatment has not been established. The duration of treatment during clinical trials, which were carried out in order to justify the use of the drug for this indication, was 36 months.

Doses for DFSP. The recommended dose for patients with DFSP is 800 mg / day.

Dose adjustment in case of adverse reactions

Non-hematologic adverse reactions. If severe non-hematologic adverse reactions appear during therapy, treatment should be discontinued until the causes of the reactions are clarified. Treatment can be restored after finding out and eliminating the causes that provoked the occurrence of adverse reactions.

At a bilirubin level more than 3 times higher than the upper limit of the norm or an increase in the level of hepatic transaminases by more than 5 times compared with the upper limit of the norm, therapy should be stopped until the elevated level of bilirubin is reduced to 1.5 times from the upper limit of the norm and the level of transaminases to 2 , 5 times from the upper limit of normal, after which treatment can be continued until the daily dose is reduced. For adult patients, the dose must be reduced from 400 to 300 mg / day or from 600 to 400 mg / day, or from 800 to 600 mg / day, in children - from 340 to 260 mg / m2/ day

Hematologic adverse reactions. With the development of severe neutropenia and thrombocytopenia, it is recommended to reduce the dose of the drug or stop treatment, as indicated in the table. 1.

Table 1
HES / HEL (initial dose 100 mg) Absolute neutrophilic number (ANF) 1 · 109/ l and / or platelets 50 · 109/ l 1. Stop therapy to ANF ≥1.5 · 109/ l and / or platelet count ≥75 · 109/ l

2. Continue therapy with the same dosage as before the reaction

Chronic phase of CML, MDS / MPZ and GISO (initial dose of 400 mg), HES / HEL (at a dose of 400 mg) ANCH 1 · 109/ l and / or platelets 50 · 109/ l 1. Stop therapy to ANF ≥1.5 · 109/ l and / or platelet count ≥75 · 109/ l

2. Continue therapy with the same dosage as before the reaction

3. In case of relapse, when ANF 1 · 109/ l and / or platelet count 50 · 109/ l, repeat step 1 and continue therapy at a dose of 300 mg

Chronic phase of CML in children (doses up to 340 mg / m2) ANCH 1 · 109/ l and / or platelets

50·109/ l

1. Discontinue therapy until ANF ≥1.5 · 109/ l and / or platelet count ≥75 · 109/ l

2. Continue therapy with the same dosage as before the reaction

3. In case of relapse, when ANF 1 · 109/ l and / or platelet count 50 · 109/ l, repeat step 1 and continue therapy at a dose of up to 260 mg / m2

Acceleration phase of CML and blast crisis, Ph+ALL (initial dose of 600 mg) andANF ​​0.5 · 109/ l and / or platelets

10·109/ l

1. Check if cytopenia is associated with leukemia (aspiration or bone marrow biopsy)

2. If cytopenia is not associated with leukemia, reduce the dose to 400 mg

3. If cytopenia persists for 2 weeks, reduce the dose to 300 mg

4. If cytopenia persists for 4 weeks and is still not associated with leukemia, discontinue therapy until ANF ≥1 · 109/ l and / or platelet count ≥20 · 109/ l, then continue treatment at a dose of 300 mg

CML acceleration phase and blast crisis in children (initial dose 340 mg / m2) andANF ​​0.5 · 109/ l and / or platelets

10·109/ l

1. Check if cytopenia is associated with leukemia (aspiration or bone marrow biopsy)

2. If cytopenia is not associated with leukemia, reduce the dose to 260 mg / m2

3. If cytopenia persists for 2 weeks, reduce the dose to 200 mg / m2

4. If cytopenia persists for 4 weeks and is still not associated with leukemia, discontinue therapy until ANF ≥1 · 109/ l and / or platelet count ≥20 · 109/ l, then continue treatment at a dose of 200 mg / m2

DFSP (800 mg dose) ANCH 1 · 109/ l and / or platelets

50·109/ l

1. Stop therapy to ANF ≥1.5 · 109/ l and / or platelet count ≥75 · 109/ l

2. Continue therapy at a dose of 600 mg

3. In case of relapse, when ANF 1 · 109/ l and / or platelet count 50 · 109/ l, repeat step 1 and continue therapy at a dose of 400 mg

andThe result after 1 month of treatment

Liver failure. Imatinib is metabolized mainly in the liver. In patients with mild, moderate and severe impaired liver function, the drug should be prescribed in the minimum recommended daily dose of 400 mg. If the treatment regimen allows, the dose can be reduced.

Table 2. Classification of liver failure
Liver failure Liver function tests
Easy Total bilirubin: 1.5 VGN *

AsAT: VGN (may be normal or VGN if total bilirubin is VGN)

Moderate Total bilirubin: 1.5–3 VGN

AsAT: some

Heavy Total Bilirubin: 3–10 VGN

AsAT: some

* VGN - the upper limit of normal

Renal failure. Patients with impaired renal function or those who are on dialysis, the drug should be prescribed in the minimum recommended initial dose of 400 mg 1 time per day. However, such patients are prescribed with caution. The dose can be reduced with intolerance to the drug or increased with insufficient effectiveness.

Elderly patients. In elderly patients, pharmacokinetics has not been studied. In clinical trials involving more than 20% of patients over the age of 65, there are no differences in the pharmacokinetics of the drug associated with age. Therefore, there are no special recommendations on the dosage of the drug for the elderly.

Children. There is no experience with the use of imatinib in children with AML under the age of 2 years, as well as in children with Ph+- ALL under the age of 1 year. Experience in treating children with MDS / MPZ, bulging DFSP, GISO and HES / HEL is very limited.

The safety and effectiveness of imatinib in children (under the age of 18 years) with MDS / MPZ, DFSP, GISO and HES / HEL during clinical trials has not been established. Currently available published data do not allow for recommendations on dosage.

Contraindications

Hypersensitivity to the active substance or excipients that make up the drug.

Side effects

Patients with a terminal stage of the malignant process may be in a condition in which it is difficult to assess the causal relationship of side effects due to the presence of a large number of symptoms of the underlying disease, its progression and the simultaneous administration of many drugs.

In clinical trials involving CML patients, drug withdrawal associated with adverse reactions to the drug was noted in 2.4% of newly diagnosed patients, in 4% of patients in the late chronic phase with ineffective interferon therapy, in 4% of patients in the acceleration phase after ineffective therapy with interferon and in 5% of patients with blast crisis after ineffective therapy with interferon. In the case of GISO,

Tags: Imatinib