Imatinib
Imatinib
Generic Name
Imatinib
Mechanism
Imatinib is a *tyrosine kinase inhibitor (TKI)* that competitively binds the ATP‑binding pocket of several oncogenic kinases:
• BCR‑ABL (the fusion protein in chronic myeloid leukemia).
• c‑KIT (stem‑cell factor receptor) and PDGFR‑α/β (platelet‑derived growth factor receptors) in gastrointestinal stromal tumors (GIST).
By occupying the ATP site, imatinib blocks autophosphorylation and downstream signaling, inducing apoptosis of malignant cells and arresting proliferation. The drug is selective for ATP‑binding sites of these kinases, thereby reducing off‑target activity compared with earlier broad‑spectrum inhibitors.
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Pharmacokinetics
- Absorption: Oral bioavailability ~% 98%; peak plasma concentration (Cmax) 1–2 h post‑dose.
- Distribution: Highly protein‑bound (~95 % to albumin and α‑1‑acid glycoprotein). Volume of distribution 60 L.
- Metabolism: Primarily hepatic via CYP3A4 → metabolites (N‑oxide, imatinib‐acid) with minimal activity.
- Excretion: 82 % fecal, 11 % urinary; half‑life ~18 h (steady‑state 24–30 h).
- Drug Interactions: Strong CYP3A4 inhibitors (ketoconazole, clarithromycin) raise plasma levels (~1.3×); strong inducers (rifampin, carbamazepine) decrease exposure (~30 %).
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Indications
- Chronic Myeloid Leukemia (CML) in chronic, accelerated, or blast phase (first‑line therapy).
- Gastrointestinal Stromal Tumors (GIST) with c‑KIT or PDGFRA mutations – first‑line for metastatic, locally advanced, or unresectable disease.
- Other: Imatinib shows activity in acute lymphoblastic leukemia (ALL) with BCR‑ABL, acute myeloid leukemia (AML) with KIT mutations, and some myeloproliferative disorders (off‑label).
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Contraindications
- Hypersensitivity to imatinib, excipients, or related compounds.
- Severe hepatic impairment (Child‑Pugh B/C) – dose adjustment or avoidance.
- Pregnancy: Category D; embryotoxic in animals – avoid unless no alternatives.
- New‑borns: significant risk of neonatal thrombocytopenia and fibrosis if maternal therapy continues past 24 wks.
- Cardiac: caution in patients with pre‑existing heart failure; monitor LVEF.
- Drug Interactions: avoid concurrent use with potent CYP3A4 inhibitors/inducers unless therapeutic drug monitoring is feasible.
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Dosing
- CML:
- *Chronic phase*: **400 mg orally once daily (or 350 mg if high albumin).
- *Accelerated/bone‑marrow blast phase*: 600 mg once daily (or split dosing 300 mg BID).
- *Second‑line (BCR‑ABL mutants)*: 800 mg once daily or split 400 mg BID.
- GIST:
- *First‑line*: 400 mg orally once daily (or 600 mg for specific KIT exon 9 mutations).
- *Post‑surgery adjuvant*: same dosing for 3 years (if high risk).
- Administration: with or without food; food may improve tolerability of GI side effects.
- Compliance: measure serum trough levels if adherence suspected (<400 ng/mL).
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Adverse Effects
| Category | Frequency | Examples | Comments |
| Common (≥10 %) | 32 % | Edema, nausea, fatigue, headache, rash, diarrhea, muscle cramps | Generally reversible; symptomatic management often adequate |
| Serious (≥1 %) | 4 % | Hepatotoxicity, myelosuppression, QT prolongation, sensorineural hearing loss, myocarditis, pleural effusion | Requires prompt evaluation; consider dose adjustment/discontinuation |
• Hand–Foot Skin Reaction: grade 1‑2 in 20‑30 %; manage with topical emollients or dose hold.
• Hepatotoxicity: ALT/AST >3× ULN with symptoms → hold, repeat AST/ALT every 2 wk.
• Cardiotoxicity: declines in EF >10 % or NYHA class III/IV → hold and refer to cardiology.
• Secondary Malignancies: leukemias, SCC of skin – long‑term surveillance essential.
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Monitoring
| Parameter | Frequency | Rationale |
| CBC + RBC indices | Daily first 2 wk, then weekly (CML) or every 2 wk (GIST) | Detect cytopenias |
| LFTs (AST, ALT, ALP, bilirubin) | Every 2 wk first month, then monthly | Monitor hepatotoxicity |
| Electrocardiogram (QTc) | Baseline, 2‑wk, then every 3 mo | QT prolongation risk |
| Echocardiography / LVEF | Baseline, 6 mo, then annually | Cardiovascular safety |
| Serum imatinib trough | 2 wk after dose escalation or in case of virologic failure | PK adherence |
| Baseline and periodic imaging (CT/MRI) | As per disease protocol | Tumor response |
| Skin assessment | Every visit | Early detection of rash or photosensitivity |
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Clinical Pearls
- First‑Line Gold Standard: Imatinib revolutionized CML; sustained deep molecular response (>MR4) correlates with durable remission.
- Dose Escalation Strategy: For BCR‑ABL mutation resistant disease, increase to 600 mg (or 800 mg) *well‑documented to restore major cytogenetic response*—neither schedule change at 400 mg alone.
- Imatinib in Pregnancy: If unavoidable, switch to a more teratogenic‑safe alternative after 24 wk because of embryo‑fixed diarrhoea, hepatic dysfunction.
- Drug–Drug Interactions: *CYP3A4 inhibition* leads to 33 % higher AUC. In patients on ketoconazole or clarithromycin consider halving imatinib dose and monitoring.
- Combination Synergy: Use nilotinib or ponatinib after imatinib failure; however, sequential therapy increases cumulative cardiotoxicity.
- Adherence Matters: Missing > 1 dose in a 7‑day period correlates with 3‑fold risk of resistance; use patient reminders or muco‑coated tablets for GI tolerance.
- Vaccination: Live attenuated vaccines contraindicated while on therapy; inactivated vaccines safe.
- Second‑Line for GIST: When imatinib fails, don’t default to high‑dose imatinib (>800 mg); switch to sunitinib or regorafenib—these bypass resistance mutations.
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• Key Takeaway: Imatinib’s precision targeting of BCR‑ABL, c‑KIT, and PDGFR has set the paradigm for tyrosine‑kinase inhibitors. Mastery of its pharmacokinetics, vigilant monitoring, and judicious dose adjustments are essential for maximizing therapeutic benefit while minimizing toxicities.