Alpelisib

• Class: PI3K alpha-specific inhibitor (Phosphatidylinositol 3-kinase inhibitor)
• Mechanism of Action:
  
  Alpelisib selectively inhibits the alpha isoform of PI3K (PI3Kα), which is involved in the PI3K/AKT/mTOR signaling pathway—a pathway frequently activated in cancers, promoting cell growth and survival. Mutations in PIK3CA gene cause pathway activation and tumor growth in HR-positive breast cancer. Alpelisib blocks this aberrant signaling, leading to decreased tumor proliferation and survival.

Indications

• HR-positive, HER2-negative, PIK3CA-mutated advanced or metastatic breast cancer.
• Used in combination with fulvestrant after progression on or after endocrine therapy.

Dosage

• Standard dose: 300 mg orally once daily with food.
• Dose reductions may be needed for toxicities such as hyperglycemia or rash.

Pharmacokinetics

• Absorption: Oral; Tmax ~2–4 hours.
• Metabolism: Mainly metabolized by CYP3A4 and non-CYP pathways.
• Elimination: Fecal and urinary.
• Half-life: ~8–9 hours.

Key Toxicities and Monitoring

• Common adverse effects:
  • Hyperglycemia (most frequent and clinically significant)
  • Rash (including serious cutaneous reactions)
  • Diarrhea
  • Nausea
  • Fatigue
• Serious concerns:
  • Severe hyperglycemia/diabetic ketoacidosis (monitor blood glucose carefully)
  • Severe rash (may require treatment interruption or steroids)
• Monitoring:
  • Blood glucose levels prior to and during treatment (fasting glucose and HbA1c recommended)
  • Skin exams and monitoring for rash
  • Liver function tests
  • Electrolytes

Drug Interactions

• Avoid strong CYP3A4 inhibitors or inducers; dose adjustment may be required.
• Use caution with other drugs that affect glucose metabolism.