Imatinib mesylate

Usage

Imatinib mesylate is prescribed for the treatment of several cancers and other conditions. These include:

• Chronic Myeloid Leukemia (CML): Specifically, Philadelphia chromosome-positive (Ph+) CML in chronic, accelerated, or blast crisis phases.
• Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL)
• Myelodysplastic/Myeloproliferative Diseases (MDS/MPD) associated with platelet-derived growth factor receptor (PDGFR) gene rearrangements.
• Systemic Mastocytosis (SM): Particularly aggressive SM (ASM), Hypereosinophilic Syndrome (HES), and/or Chronic Eosinophilic Leukemia (CEL) associated with the FIP1L1-PDGFRα fusion kinase.
• Gastrointestinal Stromal Tumors (GISTs): Kit (CD117)-positive unresectable and/or metastatic GISTs.
• Dermatofibrosarcoma Protuberans (DFSP): Unresectable, recurrent, and/or metastatic DFSP.

Pharmacological Classification: Imatinib is classified as a tyrosine kinase inhibitor (TKI). More specifically, it is a BCR-ABL tyrosine kinase inhibitor.

Mechanism of Action: Imatinib works by selectively inhibiting the BCR-ABL tyrosine kinase, an abnormal enzyme produced by the Philadelphia chromosome in CML and some other cancers. This kinase drives the growth and proliferation of cancer cells. By blocking its activity, imatinib inhibits cell growth and induces apoptosis (programmed cell death) in these cancer cells.

Alternate Names

Generic Name: Imatinib mesylate

Brand Names: Gleevec, Glivec, Imkeldi

How It Works

Pharmacodynamics: Imatinib exerts its anti-cancer effects primarily through the inhibition of BCR-ABL tyrosine kinase. It also inhibits other tyrosine kinases, including c-Kit, PDGFR, and ABL-related kinases, which are involved in various cellular processes including cell growth, differentiation, and survival. This inhibition leads to decreased cell proliferation and increased apoptosis of cancer cells.

Pharmacokinetics:

• Absorption: Imatinib is well absorbed orally, reaching peak plasma concentrations within 2-4 hours. Taking it with food enhances absorption.
• Metabolism: Primarily metabolized in the liver, mainly by CYP3A4, with minor contributions from other CYP enzymes.
• Elimination: Excreted primarily in feces via biliary excretion, with a small portion excreted in urine.

Mode of Action: Imatinib binds competitively to the ATP-binding site of BCR-ABL tyrosine kinase and other target kinases, thereby preventing ATP binding and kinase activation. This interrupts the signaling pathways responsible for the uncontrolled proliferation and survival of cancer cells.

Receptor Binding/Enzyme Inhibition/Neurotransmitter Modulation: Imatinib’s primary mechanism is enzyme inhibition, specifically targeting tyrosine kinases. There is no known significant interaction with neurotransmitters.

Dosage

Dosage is dependent on the indication and patient-specific factors. Administration is oral, typically once daily with a meal and a large glass of water.

Standard Dosage

Adults:

• CML (Chronic Phase): 400 mg orally once daily.
• CML (Accelerated/Blast Crisis): 600 mg orally once daily, or 400 mg twice daily.
• Ph+ ALL: 600 mg orally once daily.
• GIST: 400 mg orally once daily.
• DFSP: 800 mg orally once daily or 400 mg twice daily.
• HES/CEL: 100 mg once daily, or 400 mg per day, depending on severity of symptoms or the specific disorder.
• ASM: 100 to 400 mg per day.

Children: Dosing is based on body surface area (BSA), typically 340 mg/m² once daily for CML, or 260 mg/m² for most other indications. Pediatric doses are usually capped at the maximum adult dose.

Special Cases:

• Elderly Patients: Generally, no specific dose adjustments are necessary based solely on age, but close monitoring for adverse effects is recommended.
• Patients with Renal Impairment: Dose adjustments are necessary in moderate to severe renal impairment.
• Patients with Hepatic Dysfunction: Dose reduction is recommended in severe hepatic impairment.
• Patients with Comorbid Conditions: Careful assessment and individualization of dosage may be needed.

Clinical Use Cases Imatinib is not indicated for use in the listed scenarios. It is an oral anticancer agent primarily used in outpatient settings.

Dosage Adjustments

Dose adjustments are needed based on several patient-specific factors, including:

• Hematologic Toxicity (Neutropenia, Thrombocytopenia): Treatment may be temporarily held until counts recover and resumed at a reduced dose.
• Hepatotoxicity: Dose reduction or temporary interruption until liver function improves.
• Non-hematologic Adverse Reactions: Dose reduction or temporary interruption may be necessary.
• Renal/Hepatic Impairment: Dose adjustments are crucial to avoid toxicity.
• Drug Interactions: Concomitant medications may require imatinib dose adjustments.

Side Effects

Common Side Effects:

Nausea, vomiting, diarrhea, muscle cramps, fatigue, edema (swelling), rash, musculoskeletal pain, headache, abdominal pain.

Rare but Serious Side Effects:

Severe fluid retention, congestive heart failure, hepatotoxicity, myelosuppression (decreased blood cell counts), gastrointestinal perforation, severe skin reactions, tumor lysis syndrome, and left ventricular dysfunction.

Long-Term Effects:

Chronic complications can include cardiovascular problems, secondary malignancies, endocrine dysfunction, and growth retardation in children.

Adverse Drug Reactions (ADR):

Clinically significant ADRs requiring immediate intervention include anaphylaxis, angioedema, severe hepatotoxicity, myelosuppression leading to severe infections or bleeding, and cardiac events.

Contraindications

Hypersensitivity to imatinib.

Drug Interactions

Imatinib is metabolized primarily by CYP3A4. Strong CYP3A4 inducers (e.g., rifampin, phenytoin, St. John’s wort) can decrease imatinib levels, potentially reducing its efficacy. Strong CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice) can increase imatinib levels, increasing the risk of toxicity. Other clinically significant drug interactions include those with warfarin, levothyroxine, certain statins, and some antiarrhythmics.

Pregnancy and Breastfeeding

Pregnancy Safety Category: Formerly Category D, now removed as per current FDA labeling rules. Imatinib is known to be teratogenic in animals and has been associated with adverse pregnancy outcomes in humans. It should be avoided during pregnancy if possible. Contraception is crucial during treatment and for a period after discontinuation.

Breastfeeding: Imatinib is excreted in breast milk and can potentially harm a nursing infant. Breastfeeding is contraindicated during imatinib therapy and for a period after the final dose.

Drug Profile Summary

• Mechanism of Action: Tyrosine kinase inhibitor, primarily targeting BCR-ABL.
• Side Effects: Nausea, vomiting, diarrhea, edema, fatigue, myelosuppression, hepatotoxicity, and serious/rare side effects (as listed above).
• Contraindications: Hypersensitivity.
• Drug Interactions: CYP3A4 inhibitors and inducers, warfarin, levothyroxine, statins, certain antiarrhythmics.
• Pregnancy & Breastfeeding: Avoid if possible. Contraception is crucial. Breastfeeding is contraindicated.
• Dosage: Varies depending on indication and patient characteristics (see detailed section above).
• Monitoring Parameters: Complete blood counts (CBC), liver function tests (LFTs), renal function tests, cardiac function monitoring (as clinically indicated), weight monitoring.

Popular Combinations

Imatinib is sometimes used in combination with other chemotherapy agents for certain leukemias (e.g., with multi-agent chemotherapy regimens for Ph+ ALL). It is also used in combination with other targeted therapies in drug-resistant CML.

Precautions

• General Precautions: Evaluate for pre-existing medical conditions, including hepatic and renal function, cardiovascular disease, and bleeding disorders. Monitor for myelosuppression, hepatotoxicity, and fluid retention.
• Specific Populations: See “Dosage” and “Pregnancy and Breastfeeding” sections above for detailed information regarding precautions in specific populations.
• Lifestyle Considerations: Avoid grapefruit juice and other CYP3A4 inhibitors. Counsel patients about potential fatigue, dizziness, and blurred vision and their impact on daily activities.

FAQs (Frequently Asked Questions)

Q1: What is the recommended dosage for Imatinib mesylate?

A: The recommended dosage varies depending on the indication and the patient. Refer to the detailed dosage guidelines above.

Q2: What are the most common side effects?

A: The most common side effects include nausea, vomiting, diarrhea, muscle cramps, fatigue, fluid retention (edema), rash, musculoskeletal pain, headache, and abdominal pain.

Q3: What are the serious side effects to watch out for?

A: Serious side effects can include severe fluid retention, congestive heart failure, hepatotoxicity, severe myelosuppression, gastrointestinal perforation, severe skin reactions, tumor lysis syndrome, and left ventricular dysfunction.

Q4: What are the absolute contraindications for imatinib use?

A: The absolute contraindication is known hypersensitivity to imatinib or its components.

Q5: How does imatinib interact with other medications?

A: Imatinib is metabolized by CYP3A4, and its levels can be affected by CYP3A4 inhibitors and inducers. It can also interact with warfarin, levothyroxine, statins, and certain antiarrhythmics. Always review a patient’s medication list for potential interactions.

Q6: Can Imatinib be prescribed during pregnancy or breastfeeding?

A: Imatinib should generally be avoided during pregnancy due to its teratogenic potential. Breastfeeding is contraindicated during treatment and for a period afterward. Appropriate contraception is essential.

Q7: What monitoring is required during Imatinib therapy?

A: Regular monitoring of complete blood counts (CBCs), liver and renal function tests, and cardiac function (as clinically indicated) are essential. Monitoring for signs and symptoms of fluid retention, bleeding, and infections is also necessary.

Q8: How does renal or hepatic impairment affect dosing?

A: Dosage adjustments are necessary in patients with moderate to severe renal impairment and severe hepatic dysfunction. Consult specific guidelines for recommended adjustments.

Q9: What is the mechanism of action of Imatinib?

A: Imatinib inhibits BCR-ABL tyrosine kinase, and certain other tyrosine kinases, preventing downstream signalling and leading to decreased cell proliferation and increased apoptosis in specific cancer cells.

Q10: What is the role of Imatinib in managing drug-resistant CML?

A: Imatinib may still be effective in certain types of CML resistance but can be replaced by other TKIs, including second- or third-generation BCR-ABL inhibitors, when resistance develops. Combination therapy with other targeted agents is also an option.