Generic Name

Onfi

Mechanism

• Competitive inhibition of ATP binding on the BCR‑ABL fusion protein in CML and on the c‑Kit and PDGFR‑α receptors in GIST.
• Results in down‑regulation of downstream signaling (RAS‑MAPK, PI3K‑AKT, JAK‑STAT), causing cell‑cycle arrest and apoptosis.
• High specificity reduces off‑target effects common with earlier TKIs.

Pharmacokinetics

• Absorption: Oral bioavailability ~40%; reaches peak plasma concentration (Tmax) 4–8 h post‑dose.
• Distribution: Volume of distribution ~45 L; extensive tissue penetration, especially in bone marrow and GI tract.
• Metabolism: Primarily CYP3A4 mediated oxidation; minor CYP1A2, CYP2D6 contributions.
• Elimination: 10–20 % renal; 80–90 % fecal. Mean half‑life ≈ 18 h (steady‑state).
• Food increases absorption by ~33 %.

Indications

• CML in chronic, accelerated, or blast phases (first‑line TKI therapy).
• Unresectable or metastatic GIST with c‑Kit or PDGFR‑α mutations.
• Pediatric and adolescent patients (approved by FDA under specific age and stage restrictions).

Contraindications

• Known hypersensitivity to imatinib or any excipients.
• Severe hepatic impairment (Child‑Pugh C).
• Pregnancy: Category C; teratogenic potential—contraception advised.
• Important Warnings:
• Fluid retention & pericardial effusion: monitor for heart failure signs.
• Myelosuppression: neutropenia, thrombocytopenia, anemia may occur (especially with initial loading dose).
• Drug‑drug interactions: strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole) increase serum levels; strong inducers (rifampin, carbamazepine) decrease effectiveness.

Dosing

• Adults: 400 mg once daily (standard) or 800 mg once daily (high‑dose) for CML blast phase.
• GIST: 400 mg once daily after an initial 400 mg twice daily loading dose.
• Continuous 24‑hour dosing; no intermittent therapy.
• Adjust for renal dysfunction: reduce dose if CrCl <30 mL/min.
• No pausing during acute infections unless severe myelosuppression.

Adverse Effects

• Common (>10 %):
• Nausea, vomiting, diarrhea, constipation.
• Edema, headache, muscle cramps.
• Rash, pruritus, fatigue.
• Serious (>1 % but <10 %):
• Myelosuppression: neutropenia, thrombocytopenia, anemia.
• Hepatotoxicity: transaminase elevation, cholestasis.
• Cardiovascular: congestive heart failure, pericardial effusion.
• Severe hypersensitivity reactions (rare).
• Long‑term: monitor for secondary malignancies (rare).

Monitoring

• Baseline: CBC, CMP, LFTs, creatinine, ECG (ejection fraction if CHF anticipated).
• Follow‑up: CBC and CMP every 2–4 weeks for first 3 months, then every 12 weeks; LFTs monthly initially.
• Cardiac: Echocardiographic assessment if signs of heart failure; baseline and periodic in high‑risk patients.
• Drug levels: Not routine; consider if drug‑drug interactions suspected.

Clinical Pearls

• Load‑fast, keep steady: Initiating a loading dose (400 mg BID) can reduce CML blast crisis relapse, but avoid in patients with cardiac risk.
• Screen for c‑Kit mutations in GIST: on‑next‑gen sequencing improves response prediction.
• Avoid grapefruit/ grapefruit‑like products; they inhibit CYP3A4 and increase systemic exposure.
• Concurrent use with aspirin or NSAIDs should be limited due to additive myelosuppression risk.
• Pitfall in adolescents: Many under‑dosage women—ensure adherence to 400‑mg once daily and counsel on contraception.
• Combine with H2‑blockers: Good for nausea/gastro‑protective effect without interfering absorption.
• Resistance management: Bypass mutations (e.g., T315I) may require 2nd/3rd‑generation TKIs (ponatinib, nilotinib).

References

1. FDA Drug Label – Onfi (imatinib mesylate)

2. NCCN Clinical Practice Guidelines in Oncology: CML & GIST

3. Tripathi, P. (2023). “Imatinib: Clinical Update.” *J Clin Oncol.*

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