Brigatinib

Approved Indications

• Non-Small Cell Lung Cancer (NSCLC):
  Brigatinib is indicated for the treatment of adult patients with anaplastic lymphoma kinase (ALK)-positive metastatic NSCLC:
• As first-line therapy
• In patients who have progressed on or are intolerant to crizotinib

General Administration

• Route: Oral administration
• Form: Tablet
• Administration: With or without food. Swallow whole; do not crush or chew.

Adult Dosage

• Initial (Lead-in) Dose: 90 mg orally once daily for the first 7 days
• Maintenance Dose: If tolerated, increase to 180 mg orally once daily starting on day 8

Duration of Therapy

• Continue until disease progression or unacceptable toxicity.

Pediatric Use

• Safety and efficacy in pediatric patients have not been established.

Elderly

• No dosage adjustment required solely based on age.

Renal Impairment

• Mild to Moderate (eGFR ≥30 mL/min): No adjustment necessary
• Severe: Use with caution; limited data available

Hepatic Impairment

• Mild: No dose adjustment
• Moderate to Severe: Use with caution; no clinical data available

Brigatinib is a tyrosine kinase inhibitor that selectively targets ALK (anaplastic lymphoma kinase), ROS1, FLT3, and IGF-1R. By binding to the ATP-binding site of the ALK fusion protein, Brigatinib inhibits its kinase activity, thereby blocking downstream signaling pathways such as PI3K/AKT and RAS/ERK, which are critical for tumor cell proliferation and survival. This leads to apoptosis and inhibition of tumor growth in ALK-positive NSCLC cells.

• Absorption:
  Rapid absorption with peak plasma concentration (Tmax) ~1 to 4 hours post-dose
• Bioavailability:
  High; enhanced by food but not clinically significant
• Distribution:
  Volume of distribution: ~153 L
  Highly protein-bound (>90%)
• Metabolism:
  Primarily metabolized by CYP3A4; minor contribution from CYP2C8
  Forms active and inactive metabolites
• Elimination:
• Half-life: ~25 hours
• Excretion: Primarily in feces (65%) and urine (25%)

Pregnancy

• FDA Pregnancy Category: Not formally assigned
• Risk Summary: May cause fetal harm. Animal studies have shown embryo-fetal toxicity. Avoid use during pregnancy unless clearly needed.

Lactation

• Unknown if excreted in human milk
• Due to potential for serious adverse effects in nursing infants, breastfeeding is not recommended during treatment and for at least 1 week after the final dose

• Primary Class: Antineoplastic Agent
• Subclass: ALK Tyrosine Kinase Inhibitor (Second-generation)

• Known hypersensitivity to Brigatinib or any of its components
• Severe hepatic impairment (due to lack of clinical data)
• Use with strong CYP3A inducers is contraindicated

• Interstitial Lung Disease (ILD)/Pneumonitis:
  May occur early (within 1–9 days). Discontinue if suspected.
• Hypertension:
  Monitor blood pressure regularly; treat as necessary.
• Bradycardia:
  May occur; monitor heart rate, especially when used with other agents causing bradycardia.
• Visual Disturbance:
  Patients may experience blurred vision, photophobia, or visual impairment.
• Hyperglycemia:
  Monitor fasting glucose levels regularly.
• Elevated Pancreatic Enzymes:
  Monitor amylase and lipase levels; manage based on severity.
• Creatine Phosphokinase (CPK) Elevation:
  Monitor levels especially in patients with muscle symptoms.
• Embryo-Fetal Toxicity:
  Use effective contraception during treatment and for at least 4 months after the final dose.

Common Adverse Effects

• Gastrointestinal: Nausea, diarrhea, vomiting, abdominal pain
• Musculoskeletal: Myalgia, elevated CPK
• Nervous System: Headache, dizziness
• Vision: Blurred vision, photophobia
• Hematologic: Anemia
• Metabolic: Increased lipase, amylase, hyperglycemia

Serious Adverse Effects

• Interstitial lung disease
• Severe hypertension
• Bradycardia
• Pancreatitis
• Hepatotoxicity
• Rhabdomyolysis (rare)

Major Interactions

• Strong CYP3A Inhibitors (e.g., ketoconazole):
  ↑ Brigatinib levels; avoid use or reduce dose
• Strong CYP3A Inducers (e.g., rifampin, phenytoin):
  ↓ Brigatinib efficacy; contraindicated

Other Interactions

• Grapefruit juice: Avoid due to CYP3A interaction
• Bradycardia agents (e.g., beta-blockers, digoxin): Additive risk of slow heart rate
• Antihypertensives: Monitor for additive hypotensive effects

Enzyme Involvement

• Substrate of CYP3A4
• Potential inhibitor of CYP2C9 and CYP2C19 (clinically less significant)

• EMA and FDA Approvals Expanded:
  Brigatinib is now approved as first-line therapy for ALK+ NSCLC (previously only for post-crizotinib use)
• New Safety Alerts (ILD):
  Guidelines emphasize early monitoring for respiratory symptoms due to fatal ILD reports
• NCCN Guidelines (Latest):
  Recommends Brigatinib as a preferred first-line ALK inhibitor alongside alectinib and lorlatinib for ALK+ NSCLC

• Temperature: Store below 30°C
• Humidity/Light: Store in original container to protect from moisture and light
• Handling: Keep out of reach of children; do not use expired tablets
• Reconstitution: Not applicable (solid oral dosage form)