Generic Name

Xalkori

Mechanism

Xalkori competitively inhibits the ATP‑binding domain of the ALK, ROS1, and MET tyrosine kinases. By blocking phosphorylation of these receptors, it reduces downstream signaling through the RAS‑MAPK, PI3K‑AKT, and JAK‑STAT pathways, ultimately inducing apoptosis and inhibiting proliferation in malignant cells that harbor ALK or ROS1 rearrangements.

Pharmacokinetics

• Absorption – Oral bioavailability ≈ 52 % (food increases exposure by ~2×).
• Distribution – Volume of distribution ~ 300 L; binds ~ 35 % to plasma proteins.
• Metabolism – Primarily CYP3A4; minor CYP2C9 contribution.
• Elimination – Excreted mainly in feces (≈ 70 %) with a terminal half‑life of ~ 41 h.
• Drug‑Drug Interactions – Strong CYP3A4 inhibitors (e.g., ketoconazole) raise plasma levels; strong CYP3A4 inducers (e.g., rifampicin) lower exposure.

Indications

• ALK‑positive advanced or metastatic NSCLC (first‑line therapy).
• ROS1‑positive advanced or metastatic NSCLC (first‑line therapy).
• Off‑label use in ROS1 or ALK‑positive NSCLC after progression on first‑line TKI or in investigational settings.

Contraindications

Contraindications
• Known hypersensitivity to crizotinib or any excipient.

Warnings
• QT prolongation – Baseline ECG required; avoid if QTc > 450 ms or combined with other QT‑prolonging agents.
• Cardiac toxicity – Reduced left ventricular ejection fraction (LVEF) or heart failure history may contraindicate use.
• Hepatic dysfunction – Elevated ALT/AST (> 3× ULN) may necessitate dose adjustment or discontinuation.
• Hematologic effects – Neutropenia, thrombocytopenia, and anemia require monitoring.

Dosing

• Standard dose: 250 mg orally twice daily (total 500 mg/day).
• Food effect: Not required, but take with food to improve absorption.
• Hepatic impairment:
• *Mild* (Child‑Pugh A): 250 mg BID.
• *Moderate* (Child‑Pugh B): 250 mg BID or 250 mg QD.
• *Severe* (Child‑Pugh C) – Not recommended.
• Renal impairment: No dosage adjustment required; PK studies show no accumulation.

Adverse Effects

Common
• Visual disturbances (blurred vision, diplopia)
• Nausea and vomiting
• Rash (maculopapular, pruritic)
• Edema (peripheral)
• Constipation

Serious
• Hepatotoxicity (elevated transaminases, cholestatic hepatitis)
• Cardiotoxicity (QT prolongation, torsades de pointes, myocardial infarction)
• Pulmonary toxicity (interstitial lung disease, pneumonitis)
• Cytopenias (neutropenia, thrombocytopenia, anemia)

Monitoring

• Baseline: CBC with differential, CMP, liver enzymes, serum electrolytes, ECG, LVEF (echocardiogram or MUGA).
• During therapy:
• CBC and CMP q-2 weeks for first 3 months, then q-4 weeks.
• ECG and serum electrolytes q-4 weeks.
• LVEF q-3 months or as clinically indicated.
• Ophthalmologic evaluation at baseline, 4 weeks, and every 3 months thereafter.
• Imaging: Response assessment via RECIST criteria every 6–8 weeks.

Clinical Pearls

• Visual side‑effects are common but reversible; counsel patients to report sudden visual changes and avoid contact lenses while on drug.
• Drug‑Drug Interaction vigilance: Concomitant potent CYP3A4 inhibitors (ketoconazole, itraconazole) can increase crizotinib exposure by 2–3×, necessitating dose reduction; inducers (rifampicin, carbamazepine) may render the drug ineffective.
• Hepatic monitoring is crucial; a 3× ULN rise in transaminases usually prompts dose hold, while ≥ 5× ULN warrants discontinuation.
• Early cardiac screening: Baseline QTc should be ≤ 450 ms; any prolongation above 470 ms warrants hold and repeat ECG.
• Risk of interstitial lung disease is low but serious; consider CT pulmonary changes and discontinue if persistent cough or dyspnea develops.
• Resistant mutations: T790M‑like ALK mutations arise by ~ 12 months; consider next‑generation ALK TKIs (e.g., alectinib, lorlatinib) upon progression.

*Keep this succinct drug card handy for quick reference during oncology rotations or clinical rounds – it integrates essential pharmacologic data with actionable clinical pearls for practice.*