Generic Name

Imatinib mesylate

Mechanism

Imatinib mesylate (generic name of Gleevec) is a *selective ATP‑competitive inhibitor* of several tyrosine kinases, most notably the BCR‑ABL oncoprotein, c‑Kit, and platelet‑derived growth factor receptor (PDGFR). By occupying the ATP‑binding pocket of these kinases, it prevents autophosphorylation and subsequent downstream signaling, leading to apoptosis of malignant cells.
• BCR‑ABL inhibition – blocks the constitutively active fusion protein in chronic myeloid leukemia (CML).
• c‑Kit inhibition – used therapeutically in gastrointestinal stromal tumors (GIST) and systemic mastocytosis.
• PDGFR inhibition – contributes to activity in PDGFR‑positive neoplasms.

Pharmacokinetics

Indications

• Chronic myeloid leukemia (CML) – first‑line therapy in chronic and accelerated phases; also used in blast crisis when combined with chemotherapy.
• Philadelphia chromosome‑positive acute lymphoblastic leukemia (Ph+ ALL) – frontline or salvage.
• Gastrointestinal stromal tumor (GIST) – first‑line for metastatic or unresectable disease; adjuvant therapy after resection.
• Systemic mastocytosis – symptomatic control in patients with c‑Kit‑D816V mutation.
• Other off‑label – investigational in bladder cancer, renal cell carcinoma, and certain sarcomas.

Contraindications

• Contraindications
• Hypersensitivity to imatinib or any excipient.
• Severe hepatic impairment (Child‑Pugh C) – dose reduction or alternative therapy advised.
• Warnings
• Cardiotoxicity – monitor LVEF; avoid in severe heart failure.
• Fluid retention – peripheral edema, pleural effusion; treat with diuretics.
• Hepatotoxicity – periodic LFTs; discontinue if ALT/AST >5× ULN.
• Pregnancy – category D; avoid in pregnancy; effective contraception required.
• Drug interactions – potent CYP3A4 inhibitors (ketoconazole, clarithromycin) ↑ risk of toxicity; CYP3A4 inducers (rifampin) reduce efficacy.

Dosing

• CML (chronic phase) – 400 mg PO once daily (often with food).
• CML (accelerated/blast crisis) – 600 mg PO once daily; may combine with chemo.
• GIST – 400 mg PO once daily; dose may increase to 800 mg/day if disease progresses.
• Systemic mastocytosis – 400 mg PO once daily.
• Titration – increase by 200 mg increments every 4–6 weeks if inadequate response and tolerated.
• Renal insufficiency – no dose adjustment needed; monitor for toxicity.
• Administration tips – take at the same time daily; do not crush or chew tablets.

Adverse Effects

Common (≥10%)
• Nausea, vomiting, diarrhea
• Edema (peripheral)
• Muscle cramps, myalgias
• Rash, pruritus
• Anemia, neutropenia

Serious (≤5%)
• Hepatotoxicity (ALT/AST ↑, jaundice)
• Myelosuppression (febrile neutropenia)
• Cardiac dysfunction (decreased EF, heart failure)
• Pulmonary edema
• Severe hypersensitivity reactions (anaphylaxis)

Rare (<1%)
• Aplastic anemia, interstitial lung disease, ocular toxicity (cataracts), pancreatitis.

Monitoring

• Baseline & periodic
• CBC with differential (baseline, then every 2–4 weeks for 6 months).
• Liver function tests (baseline, monthly for first 3 months, then every 3 months).
• Electrolytes & renal function (baseline, then quarterly).
• Cardiac – echocardiogram or LVEF assessment at baseline and every 6 months if clinically indicated.
• Dermatologic – inspect for skin reactions; treat with topical steroids if needed.
• Compliance & toxicity – evaluate every visit; dose adjustment per response and adverse events.

Clinical Pearls

• Switching from dasatinib – patients discontinuing dasatinib should be switched to imatinib *without* dose overlap to avoid additive myelosuppression.
• Fluid retention – start low‑dose diuretics (e.g., furosemide 20 mg) at first sign of edema; consider ACE inhibitor if concomitant heart failure.
• Pharmacogenomics – CYP3A4 activity variations can markedly alter plasma levels; genotype testing may guide dosing in refractory cases.
• Bone marrow suppression – use growth factors (filgrastim) judiciously; avoid overlapping with other myelosuppressive agents.
• Pregnancy vigilance – imatinib crosses the placenta; patients on therapy should be counseled about contraceptive use; consider discontinuation if conception is planned.
• Drug interactions – avoid concomitant use of potent CYP3A4 inducers (e.g., rifampin, carbamazepine) unless therapeutic drug monitoring indicates adequate plasma exposure.

Take‑home: *Imatinib (Gleevec)* remains the cornerstone of targeted therapy for BCR‑ABL‑positive malignancies and c‑Kit‑driven tumors. Mastering its PK profile, monitoring regimen, and management of common toxicities ensures optimal patient outcomes.