Introduction
Ibrance (palbociclib) is an oral cyclin-dependent kinase (CDK) 4/6 inhibitor developed by Pfizer. It represents a significant advancement in the treatment of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced or metastatic breast cancer. Approved by the FDA in 2015, Ibrance has transformed the treatment landscape for this patient population by targeting specific cell cycle regulators.
Mechanism of Action
Palbociclib is a selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). These kinases, when activated by binding to D-cyclins, phosphorylate the retinoblastoma protein (Rb), leading to release of E2F transcription factors and progression through the G1 to S phase of the cell cycle. By inhibiting CDK4/6, palbociclib prevents Rb phosphorylation, thereby arresting the cell cycle in G1 phase and suppressing cellular proliferation. This mechanism is particularly effective in HR+ breast cancer cells, which are often dependent on CDK4/6 activity for progression through the cell cycle.
Indications
Ibrance is indicated in combination with:
- An aromatase inhibitor as initial endocrine-based therapy in postmenopausal women, or
- Fulvestrant in women with disease progression following endocrine therapy
For the treatment of HR+, HER2- advanced or metastatic breast cancer.
Dosage and Administration
Standard dosing: 125 mg orally once daily for 21 consecutive days followed by 7 days off, in 28-day cycles Administration: Taken with food to enhance absorption Dose modifications:- First dose reduction: 100 mg once daily
- Second dose reduction: 75 mg once daily
- Discontinue if further reduction below 75 mg is required
- Hepatic impairment: No adjustment needed for mild impairment; use caution in moderate to severe impairment
- Renal impairment: No adjustment needed for mild to moderate impairment (CrCl ≥30 mL/min); use caution in severe impairment
- Elderly: No specific dosage adjustment required
- Pediatric: Safety and effectiveness not established
Pharmacokinetics
Absorption: Median Tmax 6-12 hours; high-fat meal increases AUC by 21% and Cmax by 38% Distribution: Apparent volume of distribution 2,583 L; protein binding ~85% Metabolism: Primarily via CYP3A4 and sulfotransferase (SULT) 2A1 Elimination: Half-life ~29 hours; fecal excretion (74%, with <2% as unchanged drug) and renal excretion (18%) Steady-state: Achieved after 8 days of dosingContraindications
- Hypersensitivity to palbociclib or any component of the formulation
- Concomitant use with strong CYP3A inhibitors
Warnings and Precautions
Neutropenia: Severe neutropenia (Grade 3/4) occurred in 66% of patients. Monitor CBC prior to each cycle and as clinically indicated. Pulmonary embolism: Reported in 5% of patients. Monitor for signs and symptoms. Embryo-fetal toxicity: Can cause fetal harm. Advise females of reproductive potential to use effective contraception. Hepatotoxicity: Elevations in transaminases reported. Monitor liver function tests periodically. QT interval prolongation: Use caution in patients with risk factors for QT prolongation.Drug Interactions
Strong CYP3A inhibitors: Avoid concomitant use (e.g., clarithromycin, ketoconazole, ritonavir) Moderate CYP3A inhibitors: Reduce Ibrance dose to 75 mg daily (e.g., erythromycin, verapamil, diltiazem) Strong CYP3A inducers: Avoid concomitant use (e.g., rifampin, carbamazepine, St. John's wort) Gastric acid reducing agents: No clinically significant interaction with proton pump inhibitors observedAdverse Effects
Very common (≥10%):- Neutropenia (83%)
- Leukopenia (53%)
- Fatigue (41%)
- Nausea (35%)
- Anemia (31%)
- Stomatitis (28%)
- Alopecia (22%)
- Diarrhea (21%)
- Thrombocytopenia (20%)
- Severe neutropenia (66%)
- Infections (8%)
- Pulmonary embolism (5%)
- Febrile neutropenia (2%)
Monitoring Parameters
- Complete blood count prior to each cycle and on Day 14 of first two cycles
- Liver function tests at baseline and periodically
- Signs/symptoms of infection
- Signs/symptoms of pulmonary embolism
- Pregnancy testing in women of reproductive potential
- Nutritional status and hydration in patients with gastrointestinal toxicity
Patient Education
- Take with food to improve absorption
- Do not crush, chew, or break capsules
- Report signs of infection immediately (fever, chills)
- Use effective contraception during treatment and for at least 3 weeks after last dose
- Inform all healthcare providers about Ibrance use
- Do not consume grapefruit or grapefruit juice during treatment
- Report any new or worsening respiratory symptoms
- Maintain regular follow-up appointments for monitoring
- Adhere to the 21-days-on, 7-days-off schedule unless instructed otherwise
References
1. Finn RS, et al. Lancet Oncol. 2015;16(1):25-35. 2. Ibrance [package insert]. New York, NY: Pfizer Inc; 2023. 3. Turner NC, et al. N Engl J Med. 2018;379(20):1926-1936. 4. Cristofanilli M, et al. Lancet Oncol. 2016;17(4):425-439. 5. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 4.2023. 6. FDA. Ibrance approval documents. Accessed October 2023. 7. Hortobagyi GN, et al. N Engl J Med. 2022;386(5):436-446.