Usage
Palbociclib is prescribed for the treatment of hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer. It is used in combination with:
- An aromatase inhibitor (e.g., letrozole, anastrozole, exemestane) as initial endocrine-based therapy in postmenopausal women or men.
- Fulvestrant in patients with disease progression following endocrine therapy.
Pharmacological Classification: Palbociclib is a kinase inhibitor, specifically a cyclin-dependent kinase (CDK) 4 and 6 inhibitor.
Mechanism of Action: Palbociclib works by inhibiting CDK 4 and 6, which are key regulators of the cell cycle. By inhibiting these kinases, palbociclib blocks cell cycle progression in cancer cells, ultimately leading to reduced tumor growth.
Alternate Names
International Nonproprietary Name (INN): palbociclib
Brand Name: Ibrance
How It Works
Pharmacodynamics: Palbociclib exerts its anti-cancer effects by primarily inhibiting CDK4/6, leading to cell cycle arrest and ultimately tumor regression. This effect is particularly pronounced in HR-positive, HER2-negative breast cancer cells.
Pharmacokinetics:
- Absorption: Palbociclib is administered orally and is best absorbed when taken with food.
- Metabolism: Primarily metabolized by CYP3A and sulfotransferase (SULT) enzyme SULT2A1 in the liver. Palbociclib is also a weak time-dependent inhibitor of CYP3A.
- Elimination: Primarily eliminated via feces, with a small portion excreted in urine.
Mode of Action: Palbociclib selectively inhibits CDK4/6, leading to G1 cell cycle arrest by preventing the phosphorylation of retinoblastoma protein (Rb). This prevents DNA replication and cell division in susceptible cancer cells.
Receptor Binding/Enzyme Inhibition: Palbociclib directly inhibits CDK4/6 kinase activity.
Elimination Pathways: Primarily fecal excretion (approximately 73%), with minor renal excretion (approximately 17%).
Dosage
Standard Dosage
Adults:
The recommended dose is 125 mg orally once daily, taken with food, for 21 consecutive days followed by 7 days off treatment (Schedule 3/1) to complete a 28-day cycle.
Children: The safety and efficacy of Palbociclib in children and adolescents ≤18 years of age have not been established. No data are available.
Special Cases:
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Elderly Patients (≥65 years): No dose adjustment is required.
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Patients with Renal Impairment: No dose adjustment needed for mild, moderate, or severe renal impairment (creatinine clearance [CrCl] ≥15 mL/min). Insufficient data are available for patients requiring hemodialysis.
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Patients with Hepatic Dysfunction:
- Mild or moderate impairment (Child-Pugh A or B): No dose adjustment required.
- Severe impairment (Child-Pugh C): Reduce dose to 75 mg daily.
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Patients with Comorbid Conditions: Monitor closely for adverse events, particularly myelosuppression, in patients with pre-existing conditions.
Clinical Use Cases
Palbociclib’s clinical use is specifically focused on HR-positive, HER2-negative locally advanced or metastatic breast cancer. Its use is not indicated for intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations like status epilepticus or cardiac arrest.
Dosage Adjustments
Dose reductions (to 100 mg or 75 mg daily) are recommended based on individual patient tolerance and the severity of adverse events, primarily myelosuppression (neutropenia, leukopenia, anemia, thrombocytopenia).
Side Effects
Common Side Effects:
Neutropenia, leukopenia, anemia, thrombocytopenia, infections, fatigue, nausea, alopecia, stomatitis, diarrhea, vomiting, decreased appetite, arthralgia, rash.
Rare but Serious Side Effects:
Interstitial lung disease (ILD)/pneumonitis, severe myelosuppression with febrile neutropenia, hepatotoxicity, venous thromboembolism.
Long-Term Effects: Long-term side effects are still being investigated. However, prolonged myelosuppression can increase the risk of infection.
Contraindications
Hypersensitivity to palbociclib, concomitant use of strong CYP3A inducers (e.g., rifampin, carbamazepine, phenytoin).
Drug Interactions
- CYP3A Inhibitors: Strong CYP3A inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, grapefruit juice) can significantly increase palbociclib plasma concentrations. Coadministration should be avoided, or the palbociclib dose should be reduced if unavoidable.
- CYP3A Inducers: Strong CYP3A inducers (e.g., rifampin, carbamazepine, phenytoin) can decrease palbociclib concentrations. Coadministration should be avoided.
- Other Interactions: Palbociclib may increase the exposure of sensitive CYP3A substrates with a narrow therapeutic index (e.g., alfentanil, cyclosporine).
Pregnancy and Breastfeeding
Pregnancy Safety Category: Pregnancy Category D (Australia); Not assigned (US FDA). Palbociclib can cause fetal harm. Effective contraception is mandatory during treatment and for 3 weeks after the last dose for women and 14 weeks after the last dose for men.
Breastfeeding: Palbociclib is present in breast milk and may cause serious adverse reactions in infants. Breastfeeding is contraindicated during treatment and for 3 weeks after the last dose.
Drug Profile Summary
- Mechanism of Action: CDK4/6 inhibitor, blocks cell cycle progression.
- Side Effects: Neutropenia, leukopenia, infections, fatigue, nausea, alopecia.
- Contraindications: Hypersensitivity, strong CYP3A inducers.
- Drug Interactions: CYP3A inhibitors and inducers.
- Pregnancy & Breastfeeding: Contraindicated.
- Dosage: 125 mg orally daily x 21 days, then 7 days off, in a 28-day cycle.
- Monitoring Parameters: Complete blood counts (CBCs), liver function tests.
Popular Combinations
- Palbociclib + Letrozole
- Palbociclib + Fulvestrant
Precautions
- General Precautions: Monitor CBCs, liver function.
- Specific Populations: See sections on Pregnancy and Breastfeeding, Elderly patients, and patients with renal/hepatic impairment.
- Lifestyle Considerations: Avoid grapefruit and grapefruit juice. Exercise caution when driving or operating machinery due to potential fatigue and dizziness.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Palbociclib?
A: The standard dose is 125 mg orally once daily with food for 21 days followed by 7 days off treatment, as part of a 28-day cycle.
Q2: What are the most common side effects of Palbociclib?
A: Neutropenia, leukopenia, infections, fatigue, nausea, alopecia, and stomatitis.
Q3: How does Palbociclib work?
A: It inhibits CDK4/6, leading to cell cycle arrest in cancer cells.
Q4: Can Palbociclib be used during pregnancy or breastfeeding?
A: No, it is contraindicated due to potential fetal harm and the presence of the drug in breast milk.
Q5: What are the major drug interactions with Palbociclib?
A: Strong CYP3A inhibitors and inducers.
Q6: What should be monitored in patients taking Palbociclib?
A: Complete blood counts (CBCs), including neutrophil counts, and liver function tests.
Q7: What is the significance of HR-positive, HER2-negative status in breast cancer for Palbociclib use?
A: Palbociclib is specifically indicated for this subtype of breast cancer, as it shows the greatest efficacy in this patient population.
Q8: Are there any dose adjustments needed for elderly patients?
A: No dose adjustment is generally necessary for elderly patients.
Q9: What should a patient do if they miss a dose of Palbociclib?
A: They should not take an extra dose. They should take their next dose at the usual time.
Q10: Does Palbociclib have any effect on fertility?
A: While female fertility may not be significantly affected, Palbociclib can reduce fertility in men. Sperm preservation should be considered before starting therapy.
