CDK 4/6 inhibitors

1. Introduction

• CDK4/6 inhibitors are a targeted class of anticancer agents designed to block cyclin-dependent kinases 4 and 6.

• Used mainly in the treatment of hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) advanced or metastatic breast cancer.

• Represent a major advance in endocrine therapy by delaying resistance and improving survival in HR+ breast cancer when combined with hormone therapy.

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2. Mechanism of Action

• CDK4 and CDK6 are enzymes involved in regulating cell cycle progression from the G1 phase to the S phase.

• Normally, cyclin D binds to CDK4/6, leading to phosphorylation of the retinoblastoma (Rb) protein.

• Phosphorylated Rb releases E2F transcription factors, allowing transcription of genes required for DNA synthesis.

• CDK4/6 inhibitors prevent phosphorylation of Rb, halting the cell cycle in G1 phase and inhibiting tumor cell proliferation.

• Most effective in cancers with intact Rb protein.

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3. Available Agents

Palbociclib

• First CDK4/6 inhibitor approved.

• Oral capsule or tablet formulation.

• Typically used with aromatase inhibitors (letrozole, anastrozole) or with fulvestrant.

Ribociclib

• Oral tablet.

• Used in combination with aromatase inhibitors or fulvestrant.

• Requires monitoring for QT interval prolongation.

Abemaciclib

• Oral tablet.

• Can be used with endocrine therapy or as monotherapy in some cases.

• More continuous dosing schedule due to different pharmacokinetics.

• Higher incidence of gastrointestinal side effects compared to others.

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4. Pharmacokinetics

• Administration: all agents are taken orally.

• Absorption: affected by food intake to varying degrees (e.g., palbociclib should be taken with food).

• Metabolism: primarily via CYP3A4 in the liver.

• Elimination: mainly fecal excretion; renal clearance minimal.

• Half-life: ranges from ~18 to 33 hours depending on the drug.

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5. Clinical Indications

• HR+, HER2– advanced or metastatic breast cancer in postmenopausal women and men.

• Used in combination with endocrine therapy to:

  • Delay disease progression.

  • Improve progression-free survival.

  • Increase overall response rates.

• Some evidence supports adjuvant use in high-risk early breast cancer (abemaciclib).

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6. Dosing and Administration

• Palbociclib: usually given once daily for 21 days, followed by 7 days off, in a 28-day cycle.

• Ribociclib: same schedule as palbociclib (21 days on, 7 days off).

• Abemaciclib: typically given twice daily continuously without a drug-free interval.

• Dose adjustments required for toxicity or drug interactions.

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7. Adverse Effects

Hematologic

• Neutropenia (most common, especially with palbociclib and ribociclib).

• Leukopenia, anemia, thrombocytopenia.

Gastrointestinal

• Diarrhea (more prominent with abemaciclib).

• Nausea, vomiting, decreased appetite.

General

• Fatigue, alopecia, stomatitis.

Serious

• Febrile neutropenia.

• QT prolongation (ribociclib—requires ECG monitoring).

• Hepatotoxicity (elevated liver enzymes).

• Interstitial lung disease/pneumonitis (rare).

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8. Contraindications and Precautions

• Known hypersensitivity to the drug or components.

• Pregnancy and breastfeeding: potential teratogenicity; effective contraception recommended.

• Use with caution in patients with:

  • Preexisting liver impairment (dose adjustment needed).

  • Baseline neutropenia or risk factors for myelosuppression.

  • QT prolongation (especially with ribociclib).

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9. Drug Interactions

• Strong CYP3A4 inhibitors (e.g., ketoconazole, clarithromycin) increase drug levels; dose adjustment or avoidance needed.

• Strong CYP3A4 inducers (e.g., rifampin, carbamazepine) reduce drug levels and may decrease efficacy.

• Caution with other QT-prolonging drugs when using ribociclib.

• Grapefruit juice should be avoided due to CYP3A4 inhibition.

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10. Monitoring

• Complete blood counts:

  • Every 2 weeks for first 2 months, then monthly or as clinically indicated.

• Liver function tests:

  • Baseline, every 2 weeks for first 2 months, monthly for next 2 cycles, then periodically.

• ECG:

  • Baseline and periodically with ribociclib.

• Monitor for signs/symptoms of infection, diarrhea, or respiratory symptoms.

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11. Advantages in Cancer Therapy

• Targeted mechanism offers improved disease control over endocrine therapy alone.

• Oral administration improves convenience and quality of life.

• Effective in both first-line and subsequent treatment settings for HR+, HER2– disease.

• Generally well-tolerated with manageable side effect profile when monitored properly.