Palbociclib

Approved Indications (FDA/EMA):

• Hormone Receptor-Positive (HR+), Human Epidermal Growth Factor Receptor 2-Negative (HER2−) Advanced or Metastatic Breast Cancer:
• In combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women or men.
• In combination with fulvestrant in patients with disease progression following endocrine therapy.

Other Accepted Clinical Uses (Off-Label or under investigation):

• HR+/HER2− male breast cancer (clinical acceptance supported)
• Potential use in other HR+ solid tumors (e.g., ovarian cancer, endometrial cancer, though not yet formally approved)

Route: Oral (capsules or tablets taken with food)

Recommended Dose (Adults):

• Standard Dose: 125 mg once daily for 21 consecutive days, followed by 7 days off treatment (28-day cycle)
• Taken with food at the same time each day

Combination Therapy:

• Co-administer with:
• Aromatase inhibitor (e.g., letrozole, anastrozole) continuously
• Or with fulvestrant (administered as per schedule—500 mg IM on Days 1, 15, 29, then every 28 days)

Dose Adjustments:

• Grade 3 neutropenia (without fever):
• Interrupt treatment until recovery (ANC ≥1,000/mm³), then resume at the same dose or reduce if recurrent.
• Grade 4 neutropenia, febrile neutropenia, or severe non-hematologic toxicities:
• Withhold treatment until recovery, then reduce to:
• First reduction: 100 mg once daily
• Second reduction: 75 mg once daily
• Discontinue if unable to tolerate 75 mg dose

Special Populations:

• Renal Impairment:
• No dose adjustment needed for mild or moderate impairment.
• Insufficient data for severe renal impairment.
• Hepatic Impairment:
• Mild: No adjustment needed
• Moderate: Reduce to 75 mg daily
• Severe: Use not recommended
• Elderly:
• No specific dose adjustments; monitor for adverse effects
• Pediatric Use: Not indicated or approved

Palbociclib is a selective inhibitor of cyclin-dependent kinases (CDK) 4 and 6, enzymes critical for cell cycle progression from G1 to S phase. By inhibiting CDK4/6 activity, palbociclib prevents phosphorylation of the retinoblastoma (Rb) protein, resulting in cell cycle arrest at the G1 phase. This inhibition slows down the proliferation of HR+ breast cancer cells, which often rely on active CDK4/6 signaling for tumor growth. When combined with endocrine therapy, palbociclib enhances anti-proliferative effects in HR+/HER2− breast cancer.

• Absorption:
• Peak plasma concentration (Tmax): ~6–12 hours post-dose
• Absolute bioavailability: ~46% (capsule), higher for tablets
• Increased exposure with food; must be taken with food
• Distribution:
• Volume of distribution (Vd): ~2,584 L
• Plasma protein binding: ~85%
• Metabolism:
• Primarily via CYP3A4 and SULT2A1 enzymes
• Major circulating metabolite: Palbociclib sulfate (inactive)
• Elimination:
• Feces: ~74% (mostly unchanged drug)
• Urine: ~17%
• Terminal half-life: ~29 hours

• Pregnancy:
• No FDA letter category (modern labeling)
• Based on animal data, palbociclib may cause fetal harm
• Contraindicated during pregnancy
• Women of childbearing potential should use effective contraception during treatment and for at least 3 weeks after the last dose
• Men with female partners should use contraception during treatment and for 3 months after the last dose
• Lactation:
• Unknown if excreted in human milk
• Due to potential for serious adverse reactions, breastfeeding is not recommended during treatment and for 3 weeks after the last dose

• Primary Class: Antineoplastic agent
• Subclass: CDK4/6 Inhibitor
• Molecular Target: Cyclin-dependent kinases 4 and 6

• Known hypersensitivity to palbociclib or any component of the formulation
• Use of strong CYP3A4 inhibitors or inducers that cannot be avoided (unless dose adjustment is possible)
• Pregnancy and lactation

• Neutropenia:
• Most common dose-limiting toxicity; monitor CBC before and during treatment
• Infections:
• Increased risk due to myelosuppression (including fatal infections)
• Interstitial Lung Disease (ILD)/Pneumonitis:
• Rare but serious; discontinue if suspected
• QT Prolongation:
• Monitor in patients with predisposing conditions or on QT-prolonging agents
• Hepatic and renal impairment:
• Adjust dose as necessary; monitor liver function
• CYP3A4 interactions:
• Avoid grapefruit products and potent enzyme modulators

Very Common (≥10%):

• Hematologic:
• Neutropenia, leukopenia, anemia, thrombocytopenia
• Gastrointestinal:
• Nausea, stomatitis, diarrhea, vomiting
• General:
• Fatigue, infections (upper respiratory), decreased appetite
• Dermatologic:
• Alopecia

Less Common (<10%):

• Pyrexia, dizziness, peripheral edema, dry skin, dysgeusia

Rare but Serious:

• Febrile neutropenia
• Interstitial lung disease
• Pulmonary embolism
• Liver enzyme elevations

Timing & Severity:

• Neutropenia typically occurs in first 2 cycles and is reversible with dose adjustment.
• Dose-dependent side effects are manageable with supportive care.

• CYP3A4 Substrate:
• Avoid strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin): ↑ palbociclib levels and toxicity risk
• Avoid strong CYP3A4 inducers (e.g., rifampin, phenytoin): ↓ efficacy
• Gastric pH Altering Agents:
• No significant interaction with proton pump inhibitors or antacids
• Food Interaction:
• Food increases absorption; take with food to improve bioavailability
• QT Prolonging Drugs:
• Use caution if combined with other QT-prolonging agents

• NCCN and ESMO Guidelines: Continue to recommend palbociclib with endocrine therapy as first-line for HR+/HER2− metastatic breast cancer
• Recent FDA Label Updates:
• Clarified dose modification instructions for neutropenia
• Expanded data supporting use in male breast cancer patients
• Ongoing Studies:
• Exploring adjuvant use in early-stage HR+/HER2− breast cancer
• Investigating in combination with PI3K or mTOR inhibitors

• Temperature: Store at 20°C to 25°C (68°F to 77°F)
• Excursions permitted between 15°C to 30°C
• Humidity: Protect from excessive moisture
• Light Protection: Store in original container
• Handling Precautions:
• Do not crush or chew capsules/tablets
• Handle with care; wash hands after handling
• Disposal: Follow hazardous drug disposal procedures