Abeclib

• FDA-Approved Indications:
• HR-positive, HER2-negative advanced or metastatic breast cancer:
• In combination with an aromatase inhibitor as initial endocrine-based therapy in postmenopausal women and men.
• In combination with fulvestrant in patients with disease progression following endocrine therapy.
• As monotherapy in adult patients who have previously received endocrine therapy and chemotherapy in the metastatic setting.
• Early breast cancer (EBC):
• In combination with tamoxifen or an aromatase inhibitor for adjuvant treatment of adult patients with HR-positive, HER2-negative, node-positive early breast cancer at high risk of recurrence.
• Clinically Accepted Off-label Use:
• Brain metastases in breast cancer (investigational).
• Combination therapy in neoadjuvant settings (studied but not yet formally approved).

• Advanced/Metastatic Breast Cancer (in combination):
• 150 mg orally twice daily.
• Continue until disease progression or unacceptable toxicity.
• Monotherapy:
• 200 mg orally twice daily.
• Early Breast Cancer (Adjuvant):
• 150 mg orally twice daily for 2 years, in combination with endocrine therapy.
• Administration Notes:
• Can be taken with or without food.
• Swallow tablets whole; do not crush, chew, or split.
• Dose Adjustments:
• Hepatic impairment (Child-Pugh B/C): Reduce starting dose to 150 mg twice daily.
• Renal impairment: No adjustment needed for mild/moderate impairment; use with caution in severe cases.
• Elderly: No specific adjustment, but monitor more frequently due to higher risk of neutropenia.
• Pediatric: Safety and efficacy not established.

Abemaciclib is an orally bioavailable, selective inhibitor of cyclin-dependent kinases 4 and 6 (CDK4/6). These kinases, when complexed with D-type cyclins, phosphorylate the retinoblastoma protein (Rb), allowing progression from G1 to S phase in the cell cycle. Inhibition of CDK4/6 leads to cell cycle arrest at the G1 phase, thus halting proliferation of hormone receptor-positive breast cancer cells that depend on this pathway. Abemaciclib demonstrates continuous target inhibition due to its sustained exposure profile.

• Absorption:
• Oral bioavailability ~45%.
• Time to peak plasma concentration: ~8 hours.
• Food has minimal effect on overall exposure.
• Distribution:
• Volume of distribution: ~690 L.
• Plasma protein binding: ~96.3%.
• Metabolism:
• Primarily metabolized by CYP3A4.
• Major metabolites: N-desethylabemaciclib and hydroxy derivatives (some retain activity).
• Excretion:
• Feces (81%), urine (3%).
• Terminal half-life: ~18 hours.
• Steady-State: Reached in ~5 days with twice-daily dosing.

• Pregnancy:
• Not recommended during pregnancy.
• Animal studies show embryo-fetal toxicity and teratogenicity.
• Can cause fetal harm if administered to a pregnant woman.
• Use effective contraception during treatment and for 3 weeks after the last dose.
• Lactation:
• Unknown if excreted in human milk.
• Due to potential for serious adverse reactions in breastfeeding infants, discontinue breastfeeding during treatment and for 3 weeks after the final dose.
• Data Status:
• No adequate data in human pregnancy; caution strongly advised.

• Primary Class: Antineoplastic Agent
• Subclass: CDK4/6 Inhibitor

• Known hypersensitivity to abemaciclib or any of its components.
• Severe hepatic impairment (if not adjusted).
• Concomitant use with strong CYP3A4 inducers (relative contraindication due to reduced efficacy).

• Neutropenia: Monitor complete blood counts regularly; dose interruption/reduction may be needed.
• Diarrhea: Common and can be severe; initiate anti-diarrheal agents (e.g., loperamide) and maintain hydration.
• Hepatotoxicity: Monitor liver function tests (ALT/AST); discontinue for persistent grade 3–4 elevations.
• Venous Thromboembolism (VTE): Increased risk; assess and manage promptly if symptoms occur.
• Interstitial Lung Disease (ILD)/Pneumonitis: Rare but serious; monitor for pulmonary symptoms.
• QT prolongation: Monitor in patients with cardiac risk factors or on QT-prolonging drugs.

• Common (≥10%):
• Hematologic: Neutropenia, leukopenia, anemia.
• GI: Diarrhea, nausea, vomiting, decreased appetite.
• General: Fatigue, infections, weight loss.
• Hepatic: Elevated ALT/AST.
• Serious/Rare:
• Febrile neutropenia
• Pulmonary embolism
• ILD/pneumonitis
• Severe hepatotoxicity
• Dose Dependence:
• Hematologic toxicities and diarrhea increase with higher doses; monitored closely during initial cycles.

• Major Interactions:
• CYP3A4 inhibitors (e.g., ketoconazole): ↑ Abemaciclib exposure — reduce dose.
• CYP3A4 inducers (e.g., rifampin, carbamazepine): ↓ Abemaciclib efficacy — avoid if possible.
• P-gp substrates (e.g., digoxin): Abemaciclib may increase levels — monitor.
• Food/Alcohol:
• No known significant interaction with food or alcohol.
• Metabolic Enzymes:
• Primarily metabolized by CYP3A4; caution with agents affecting this pathway.

• FDA Update (2021–2023):
• Abemaciclib approved for adjuvant treatment of early breast cancer (EBC) with high recurrence risk.
• NCCN & ASCO Guidelines:
• Recommended as standard-of-care in HR+/HER2- metastatic breast cancer in combination with endocrine therapy.
• Highlighted in early breast cancer protocols for high-risk patients.
• EMA Update:
• Approved for extended use in adjuvant setting in Europe.

• Temperature: Store at 20°C to 25°C (68°F to 77°F).
• Excursions: Permitted between 15°C and 30°C (59°F to 86°F).
• Handling:
• Protect from moisture; dispense in original container.
• Do not crush or split tablets.
• Special Precautions:
• Keep out of reach of children.
• No refrigeration or reconstitution required.