What Is Imatinib?

Imatinib, a tyrosine kinase inhibitor, is a small molecule protein kinase inhibitor that has the effect of blocking one or more protein kinases. Clinically used to treat chronic myelogenous leukemia and malignant gastrointestinal stromal tumors.

Imatinib, a tyrosine kinase inhibitor, is a small molecule protein kinase inhibitor that has the effect of blocking one or more protein kinases. Clinically used to treat chronic myelogenous leukemia and malignant gastrointestinal stromal tumors.

Chinese name

Imatinib

English name

Imatinib

nickname

Imatinib intermediates; imatinib

Chemical formula

C29H31N7O

Molecular weight

493.60

CAS Registry Number

152459-95-5

English alias

IMA-3

Introduction

Chinese name: Imatinib

Chinese alias: imatinib intermediate; imatinib; 4-[(4-methyl-1-piperazinyl) methyl] -N- [4-methyl-3- [4- (3- Pyridyl) -2-pyrimidinyl] amino] phenyl] benzamide

English name: Imatinib

English alias: IMA-3; IMATINIB-D3; AKOS 91378; Imatinib Base; 4-[(4-methylpiperazin-1-yl) methyl] -N- (4-methyl-3-{[4- (pyridin-3- yl) pyrimidin-2-yl] amino} phenyl) benzamide; 4-[(4-methylpiperazin-1-yl) methyl] -N- (4-methyl-3-{[4- (pyridin-3-yl) pyrimidin -2-yl] amino} phenyl) benzamide methanesulfonate (1: 1)

Chemical Structure

Imatinib

CAS number: 152459-95-5

Molecular formula: C29H31N7O

Molecular weight: 493.60

Physical and chemical properties

Density: 1.30

Melting point: 113 ° C

Boiling point: 451 ° C

Flash point: 196 ° C

Vapor pressure: 6.03E-24mmHg at 25 ° C ^[1]

Imatinib synthetic route

N- (5-amino-2-methylphenyl) -4 (3-pyridyl) -2-pyrimidinamine and 4- (4-methylpiperazinemethyl) benzoyl chloride are dissolved in pyridine at room temperature and Stir under nitrogen. Concentrated under reduced pressure, added water, cooled, filtered, and the cake was dried under vacuum. Dichloromethane-methanol was added, and then filtered. The product imatinib was obtained. ^[1]

Imatinib imatinib related drug label information

Dosage form and specifications

Imatinib mesylate capsules: 100mg / capsule.

Store

Store below 30 ° C.

Pharmacological action

This product is a derivative of phenylpyrimidine and belongs to a new type of tyrosine kinase inhibitor. About 95% of patients with chronic myelocytic leukemia (CML) have a positive ph chromosome, that is, a segment from the proto-oncogene ABL of chromosome 9 to chromosome 22 is called a breakpoint clustering region. (BCR) oncogene, the two genes are recombined together to produce the fusion protein p-210. Compared with the normal C-ABL protein p-150, p-210 has higher tyrosine kinase activity and can stimulate Leukocytes proliferate and cause leukemia. This product can strongly inhibit the activity of ABL tyrosine kinase in vivo and in vitro, specifically inhibit the expression of ABL and the proliferation of BCR-ABL cells, so it can be used to treat CML. In addition, this product can still inhibit platelet-derived growth factor (PDGF) and stem cell factor (SCF) receptor tyrosine kinase, and can inhibit PDGF and SCF-mediated biochemical reactions, but not Affects the signaling of other stimulating factors (such as epidermal growth factor, etc.).

Pharmacokinetics

This product is easy to be absorbed orally. After 2 to 4 hours, the blood concentration reaches a peak, the oral bioavailability is 98%, and the protein binding rate is 95%. Preclinical studies have shown that this product does not easily penetrate the blood-cerebrospinal fluid barrier. Drugs are mainly metabolized in the liver into pharmacologically active metabolites (N-desmethylpiperazine derivatives). The half-life of the original drug and the metabolite are 18h and 40h, respectively. Within 7 days after oral administration of this product, about 81% is excreted from the body (68% is excreted in feces and 13% is excreted in urine), of which about 25% is the drug form (5% in urine and 20% in stool).

Indication

For the treatment of chronic myelogenous leukemia (CML). It is also used to treat CD117 positive gastrointestinal stromal cell tumor (GIST).

Contraindications

1. Those who are allergic to this product are prohibited.

2. Use with caution in patients with liver dysfunction.

3. Use with caution in severe heart failure.

4. Animal experiments show that this product is teratogenic, and there is still lack of medication information for pregnant women. Pregnant women should be used with caution.

5. Can be secreted in large quantities from human and animal milk, and its distribution in human milk is unclear. Use with caution in lactating women.

6. Bone marrow suppression should be used with caution.

7. Use with caution in patients with viral or bacterial infections.

8. Gastrointestinal disorders should be used with caution.

Precautions

1. Liver function (including aminotransferase, bilirubin, and alkaline phosphatase) should be checked before treatment, and it can be reviewed once a month afterwards.

2. In the first month of treatment, check the blood routine every week, and in the second month, check every two weeks.

3. It is recommended to monitor weight regularly.

Adverse reactions

1. Hematological system: neutropenia (14%), thrombocytopenia (14%), and anemia (11%) are visible. Neutropenic fever and pancytopenia are also common.

2. Metabolic endocrine system: lack of appetite, rare increase in appetite, dehydration, elevated blood uric acid and potassium, or decreased potassium and sodium.

3. Neuropsychiatric system: common headache (11%), dizziness, taste disorders, insomnia, rare hemorrhagic stroke, syncope, peripheral neuropathy, hypoesthesia, lethargy, migraine and depression.

4. Eyes and ears: Conjunctivitis and tears are common, and eye irritation, blurred vision, conjunctival hemorrhage, dry eyes, periorbital edema, and abnormal ears and labyrinths are rare.

5. Cardiovascular system: Rarely heart failure, pulmonary edema, tachycardia, hypertension, hypotension, flushing of the skin, coldness of the limbs and hematoma.

6. Respiratory system: pleural effusion, epistaxis, dyspnea and cough are rare.

7. Digestive system: common nausea (56%), vomiting (33%), diarrhea (24%), indigestion (12%), abdominal pain, bloating, constipation, dry mouth, rare gastrointestinal bleeding, ascites, gastric ulcers, Hepatic abnormalities such as gastritis, gastroesophageal reflux, oral ulcers, elevated aminotransferases, and elevated bilirubin.

8. Skin: common general edema (30%), various types of dermatitis and rash (about 25%), pruritus skin, erythema, dry skin, hair loss, night sweats. Rare spots, sweating, hives, broken nails, photosensitivity reactions, and purpura are rare.

9. Musculoskeletal system: muscle cramps (33%), joint swelling and pain (25%), sciatica are rare.

10. Urogenital system: Rarely increased serum creatinine, renal failure, feminization of male breasts, breast enlargement, and scrotal edema.

11. Others: Common water retention (10%), fever, fatigue, chills, and weight gain. Rare general malaise, bleeding, weight loss, sepsis, pneumonia, herpes virus infection and so on.

Dosage

CML rapid and accelerated phase: oral, the recommended starting dose is 600mg each time, once a day, if the condition continues to develop after treatment (therapeutic effect has not been achieved after at least 3 months of treatment), and the patient does not have serious adverse reactions Time, it can be increased to 400mg each time, 2 times / d. When hematological adverse reactions occur, with a neutrophil count (ANC) of less than 0.5 × 10 / L or a platelet count of less than 10 × 10 / L, it is recommended to reduce the dose to 400 mg per day. If blood cell reduction continues for 2 weeks, it should be further reduced to 300 mg per day; if blood cell reduction persists for 4 weeks, treatment should be stopped until ANC is higher than 1.0 × 10 / L and platelet count is higher than 20 × 10 / L, and then resumed Medication.

CML chronic phase of interferon treatment failure: oral, starting dose is 400mg each time, once a day, if the disease continues to develop and the patient does not have serious adverse reactions after treatment, it can be increased to 600mg per day. The drug should be discontinued when the ANC is less than 1.0 × 10 / L and the platelet count is less than 50 × 10 / L. The drug can be resumed only when the ANC is higher than 1.5 × 10 / L and the platelet count is higher than 75 × 10 / L. The dose is 400 mg per day. When the ANC or platelet count decreases again, the drug will be resumed later. The dose should be reduced to 300 mg per day.

medicine interactions

CYP3A4 inhibitor, a drug that can change the plasma concentration of imatinib: After a single dose of a ketoconazole (CYP3A4) inhibitor was given to healthy subjects at the same time, the drug exposure to imatinib increased significantly (average maximum plasma concentration (Cmax ) And the area under the imatinib curve (AUC) can increase by 26% and 40%, respectively). No prior experience with other CYP3A4 inhibitors such as itraconazole, erythromycin and clarithromycin.
CYP3A4 inducer: After taking rifampin in healthy volunteers, the clearance of imatinib increased by 3.8 times (90% confidence interval = 3.5-4.3 times), but Cmax, AUC (0-24) and AUC (0-8 ) Decreased by 54%, 68% and 74% respectively. In clinical studies, it was found that the plasma concentration of imatinib decreased after concomitant administration of phenytoin, resulting in a reduction in efficacy. After taking enzyme-inducing anti-epileptic deugs (EIAEDs) such as carbamazepine, oxcarbazepine, phenytoin, fosphenytoin, phenobarbital, and deoxyphenpytole, while taking this product Similar results were observed in patients with malignant glioma. Compared with taking EIAEDs at the same time, the AUC of imatinib is reduced to 73%. Other CYP3A4 inducers such as dexamethasone, catarrhizine, and phenobarbital may have similar problems. Therefore, imatinib should be avoided. Nylon and CYP3A4 inducer are taken at the same time. In two published studies, the combination of imatinib with St John's wort extract can reduce the AUC of this product by 30-32%.
Imatinib mesylate can change the plasma concentration of the following drugs. Imatinib increases the average Cmax and AUC of simvastatin (CYP3A4 substrate) by 2 and 3.5 times, respectively. It should be kept in mind that imatinib can increase the plasma concentration of other drugs metabolized by CYP3A4 (such as benzodiazepines, dihydropyridines, calcium channel antagonists, and other HMG-CoA reductase inhibitors, etc.). Therefore, caution should be taken when taking this medicine and CYP3A4 substrates (such as cyclosporine, pimozide) with narrow therapeutic windows at the same time.
Imatinib also inhibits CYP2D6 activity in vitro at concentrations similar to those that inhibit CYP3A4 activity, so it is possible to increase systemic exposure to CYP2D6 substrates when taken concurrently with imatinib mesylate, although No special research has been done and it is recommended to use it with caution.
Imatinib can also inhibit the activity of CYP2C9 and CYP2C19 in vitro, and prolonged prothrombin time can be seen after taking warfarin. Therefore, at the beginning or end of imatinib mesylate treatment or changing the dose, if coumarin is also used at the same time, the prothrombin time should be monitored for a short time.
The inhibitory effect of imatinib 400 mg twice daily on CYP2D6-induced metoprolol metabolism was very weak, and Cmax and AUC of metoprolol increased by about 23%. The combination of imatinib with a CYP2D6 inducer such as metoprolol does not appear to have any risk factors for drug-drug interactions, and dose adjustments are not necessary.
In vitro experiments show that imatinib can inhibit the 0-glucuronidation of acetaminophen.
Patients should be warned to avoid over-the-counter and prescription drugs containing acetaminophen (see [Cautions]).

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