Usage
Abemaciclib is prescribed for certain types of breast cancer:
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Early breast cancer: As adjuvant therapy in combination with endocrine therapy (tamoxifen or an aromatase inhibitor) for patients with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative, node-positive early breast cancer at high risk of recurrence.
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Advanced or metastatic breast cancer:
- In combination with an aromatase inhibitor as initial endocrine-based therapy for HR-positive, HER2-negative disease.
- In combination with fulvestrant for HR-positive, HER2-negative disease after progression on endocrine therapy.
- As a single agent (monotherapy) for HR-positive, HER2-negative disease after progression on endocrine therapy and prior chemotherapy in the metastatic setting.
Pharmacological Classification: Kinase inhibitor, specifically a cyclin-dependent kinase (CDK) 4 and 6 inhibitor.
Mechanism of Action: Abemaciclib selectively inhibits CDK4 and CDK6, which are crucial regulators of the cell cycle. By inhibiting these kinases, abemaciclib blocks cell cycle progression in the G1 phase, thereby suppressing the proliferation of cancer cells.
Alternate Names
International Nonproprietary Name (INN): Abemaciclib
Brand Name: Verzenio
How It Works
Pharmacodynamics: Abemaciclib primarily exerts its anticancer effects by inhibiting CDK4 and CDK6, leading to cell cycle arrest and reduced tumor growth.
Pharmacokinetics:
- Absorption: Well-absorbed orally. A high-fat meal can slightly increase absorption, but this is not considered clinically significant.
- Metabolism: Primarily metabolized in the liver via CYP3A4.
- Elimination: Excreted mainly in the feces, with a small amount in urine.
Mode of Action: Abemaciclib competitively binds to the ATP-binding pockets of CDK4 and CDK6, preventing their activation and subsequent phosphorylation of retinoblastoma protein (Rb). This inhibition of Rb phosphorylation leads to cell cycle arrest in the G1 phase.
Receptor Binding/Enzyme Inhibition: Abemaciclib inhibits the enzymatic activity of CDK4 and CDK6.
Elimination Pathways: Primarily hepatic metabolism via CYP3A4, followed by fecal excretion.
Dosage
Standard Dosage
Adults:
- Early breast cancer (with endocrine therapy): 150 mg orally twice daily for up to 2 years, or until disease recurrence or unacceptable toxicity.
- Advanced or metastatic breast cancer (with fulvestrant or an aromatase inhibitor): 150 mg orally twice daily.
- Advanced or metastatic breast cancer (monotherapy): 200 mg orally twice daily.
Children: Use and dose must be determined by a doctor.
Special Cases:
- Elderly Patients: No specific dose adjustment is recommended, but closer monitoring is advised.
- Patients with Renal Impairment: No dose adjustment is necessary for mild or moderate impairment. Use in severe renal impairment has not been studied.
- Patients with Hepatic Dysfunction: No dose adjustment is necessary for mild or moderate impairment. For severe hepatic impairment (Child-Pugh C), reduce the dosing frequency to once daily.
- Patients with Comorbid Conditions: Dose adjustments or closer monitoring may be needed based on specific comorbid conditions.
Clinical Use Cases
Abemaciclib is specifically indicated for breast cancer treatment, not typically used in settings like intubation, surgical procedures, mechanical ventilation, ICU use, or emergency situations.
Dosage Adjustments
Dose reductions may be required based on individual tolerance and adverse events, especially diarrhea, neutropenia, and hepatotoxicity.
Side Effects
Common Side Effects:
Diarrhea, neutropenia, infections, fatigue, nausea, vomiting, abdominal pain, decreased appetite, headache, dizziness, alopecia.
Rare but Serious Side Effects:
Interstitial lung disease, venous thromboembolism, hepatotoxicity, severe neutropenia leading to serious infections.
Long-Term Effects:
Long-term side effects are still being investigated.
Adverse Drug Reactions (ADR):
Severe diarrhea, neutropenia with fever, signs of interstitial lung disease (e.g., dyspnea, cough, fever), venous thromboembolism (e.g., pain, swelling in extremities).
Contraindications
No absolute contraindications.
Drug Interactions
- Strong CYP3A4 Inhibitors: Avoid concomitant use of ketoconazole. Reduce the abemaciclib dose with other strong CYP3A4 inhibitors (e.g., itraconazole, clarithromycin, ritonavir).
- Strong CYP3A4 Inducers: Avoid concomitant use of strong CYP3A4 inducers (e.g., rifampin, St. John’s wort, phenytoin) as they may decrease abemaciclib efficacy.
- Other Medications: Consult drug interaction resources for a comprehensive list.
- Grapefruit products: Avoid grapefruit and grapefruit juice as they can increase abemaciclib concentrations.
Pregnancy and Breastfeeding
- Pregnancy Safety Category: Abemaciclib can cause fetal harm. Women of childbearing potential should use effective contraception during treatment and for at least 3 weeks after the last dose.
- Breastfeeding: Breastfeeding is not recommended during treatment and for at least 3 weeks after the last dose.
Drug Profile Summary
- Mechanism of Action: CDK4/6 inhibitor, leading to cell cycle arrest.
- Side Effects: Diarrhea, neutropenia, infections, fatigue.
- Contraindications: None.
- Drug Interactions: CYP3A4 inhibitors and inducers, grapefruit.
- Pregnancy & Breastfeeding: Contraindicated in pregnancy, not recommended while breastfeeding.
- Dosage: See detailed dosage section above.
- Monitoring Parameters: Complete blood counts (CBCs), liver function tests (LFTs), signs and symptoms of interstitial lung disease and venous thromboembolism.
Popular Combinations
Abemaciclib is commonly used in combination with:
- Aromatase inhibitors (e.g., anastrozole, letrozole, exemestane): For HR-positive, HER2-negative advanced or metastatic breast cancer.
- Fulvestrant: For HR-positive, HER2-negative advanced or metastatic breast cancer after progression on endocrine therapy.
- Tamoxifen: For HR-positive, HER2-negative, node-positive, high-risk early breast cancer.
- GnRH agonists: In pre/perimenopausal women and men receiving abemaciclib with an aromatase inhibitor or fulvestrant.
Precautions
- Monitor for diarrhea, neutropenia, hepatotoxicity, interstitial lung disease, and venous thromboembolism.
- Women of childbearing potential should use effective contraception.
- Men should be counseled on potential fertility impairment.
FAQs (Frequently Asked Questions)
Q1: What is the recommended dosage for Abemaciclib?
A: The dosage depends on the indication: 150 mg twice daily with endocrine therapy (early breast cancer or advanced/metastatic), 200 mg twice daily as monotherapy (advanced/metastatic).
Q2: What are the most common side effects?
A: Diarrhea, neutropenia, infections, and fatigue.
Q3: What should be done if a patient develops severe diarrhea while on abemaciclib?
A: Promptly initiate anti-diarrheal medication (e.g., loperamide), increase fluid intake, and consider dose interruption or reduction.
Q4: What are the key drug interactions to be aware of?
A: Strong CYP3A4 inhibitors and inducers, and grapefruit products.
Q5: Can abemaciclib be used in pregnant or breastfeeding women?
A: Abemaciclib is contraindicated during pregnancy and not recommended during breastfeeding.
Q6: What monitoring is recommended during abemaciclib treatment?
A: Regular CBCs, LFTs, and monitoring for signs and symptoms of interstitial lung disease and venous thromboembolism.
Q7: How does abemaciclib work differently from other CDK4/6 inhibitors?
A: While all CDK4/6 inhibitors target the same kinases, subtle differences in their binding affinities and pharmacokinetic profiles can lead to variations in efficacy and toxicity.
Q8: What should I do if a patient experiences signs of interstitial lung disease?
A: Immediately discontinue abemaciclib and evaluate the patient for interstitial lung disease.
Q9: What is the role of abemaciclib in adjuvant therapy for early breast cancer?
A: It is used in combination with endocrine therapy to reduce the risk of recurrence in high-risk patients.
Q10: Are there any specific dietary restrictions while taking abemaciclib?
A: Patients should avoid grapefruit and grapefruit juice. No other specific dietary restrictions are required, and the medication can be taken with or without food.
