Introduction
Verzenio (abemaciclib) is an oral cyclin-dependent kinase (CDK) 4/6 inhibitor developed by Eli Lilly and Company. 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 2017, Verzenio offers a targeted therapeutic approach that disrupts cell cycle progression in cancer cells.
Mechanism of Action
Verzenio works through selective inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6). These kinases, when activated by D-cyclins, phosphorylate the retinoblastoma protein (Rb), leading to release of E2F transcription factors and progression from the G1 to S phase of the cell cycle. By inhibiting CDK4/6, abemaciclib induces G1 phase arrest in susceptible cancer cells, preventing DNA synthesis and cellular proliferation. Unlike other CDK4/6 inhibitors, abemaciclib demonstrates continuous target inhibition and can be administered as monotherapy due to its more potent CDK4/6 inhibition profile.
Indications
Verzenio is FDA-approved for: 1. HR+/HER2- advanced or metastatic breast cancer in combination with an aromatase inhibitor as initial endocrine-based therapy 2. HR+/HER2- advanced or metastatic breast cancer in combination with fulvestrant following disease progression on endocrine therapy 3. HR+/HER2- advanced or metastatic breast cancer as monotherapy following disease progression on endocrine therapy and prior chemotherapy in the metastatic setting
Dosage and Administration
Standard dosing:- Combination therapy: 150 mg orally twice daily
- Monotherapy: 200 mg orally twice daily
- Taken with or without food
- Tablets should be swallowed whole with water
- Dosing interval should be approximately 12 hours
Required for management of adverse reactions including diarrhea, neutropenia, hepatotoxicity, and other toxicities. Dose reductions follow a stepwise approach (200 mg → 150 mg → 100 mg twice daily).
Special populations:- Hepatic impairment: Reduce starting dose for moderate or severe impairment
- Renal impairment: No dosage adjustment needed for mild to moderate impairment; use caution in severe impairment
- Geriatric patients: No dosage adjustment required
- Pediatric patients: Safety and effectiveness not established
Pharmacokinetics
Absorption: Median time to peak plasma concentration (Tmax) is 4-6 hours. Administration with high-fat meal increases AUC by 9% and Cmax by 26%. Distribution: Mean apparent volume of distribution is 690 L. Protein binding is approximately 96%. Metabolism: Primarily metabolized by CYP3A4 to active metabolites (M2, M20, M18). Elimination: Mean elimination half-life is 18.3 hours. Excretion is primarily fecal (81%) with minor renal elimination (3%).Contraindications
1. Hypersensitivity to abemaciclib or any component of the formulation 2. Pregnancy (based on mechanism of action and animal data)
Warnings and Precautions
Diarrhea: Occurred in 86% of patients, with severe diarrhea (Grade 3) in 13%. May lead to dehydration and infection. Requires early intervention with antidiarrheal agents and dose modification. Neutropenia: Occurred in 46% of patients, with Grade 3/4 in 24%. Monitor complete blood counts prior to initiation and every 2 weeks for first 2 months. Hepatotoxicity: Drug-induced liver injury reported. Monitor liver function tests prior to initiation and every 2 weeks for first 2 months. Venous Thromboembolism: Deep vein thrombosis and pulmonary embolism reported. Monitor for signs and symptoms. Interstitial Lung Disease/Pneumonitis: Reported in clinical trials. Monitor for pulmonary symptoms and discontinue if suspected. Embryo-Fetal Toxicity: Can cause fetal harm. Verify pregnancy status prior to initiation and advise effective contraception.Drug Interactions
Strong CYP3A inhibitors: Avoid concomitant use with strong inhibitors (e.g., ketoconazole, itraconazole, clarithromycin). If unavoidable, reduce Verzenio dose. Strong CYP3A inducers: Avoid concomitant use with strong inducers (e.g., rifampin, carbamazepine, St. John's wort). Gastric acid-reducing agents: Proton pump inhibitors and H2-receptor antagonists may reduce abemaciclib exposure. Separate administration by at least 2 hours.Adverse Effects
Most common (≥20%):- Diarrhea (86%)
- Neutropenia (46%)
- Nausea (45%)
- Fatigue (39%)
- Infections (31%)
- Abdominal pain (29%)
- Anemia (25%)
- Vomiting (24%)
- Alopecia (22%)
- Decreased appetite (21%)
- Headache (20%)
- Severe diarrhea (13%)
- Neutropenia (24% Grade 3/4)
- Venous thromboembolism (5%)
- Hepatotoxicity (2-3%)
- Interstitial lung disease (1-2%)
Monitoring Parameters
1. Complete blood counts: Prior to initiation, every 2 weeks for first 2 months, then monthly 2. Liver function tests: Prior to initiation, every 2 weeks for first 2 months, then as clinically indicated 3. Renal function: Baseline and periodic assessment 4. Signs/symptoms of diarrhea: At each visit and as needed 5. Signs/symptoms of infection: Continuous monitoring 6. Signs/symptoms of venous thromboembolism: Continuous monitoring 7. Pulmonary symptoms: Continuous monitoring for interstitial lung disease 8. Pregnancy status: Prior to initiation in women of reproductive potential
Patient Education
Key points to discuss:- Take medication exactly as prescribed at approximately 12-hour intervals
- Report diarrhea immediately; keep antidiarrheal medication available
- Monitor for signs of infection (fever, chills) and report promptly
- Report unusual bleeding or bruising
- Be aware of potential liver problems (yellowing skin/eyes, dark urine)
- Use effective contraception during treatment and for at least 3 weeks after final dose
- Inform all healthcare providers about Verzenio use
- Do not breastfeed during treatment and for at least 3 weeks after final dose
- Maintain regular follow-up appointments and laboratory monitoring
- Report any new or worsening respiratory symptoms
References
1. FDA Prescribing Information: Verzenio (abemaciclib). September 2023. 2. Goetz MP, et al. MONARCH 3: Abemaciclib as initial therapy for advanced breast cancer. J Clin Oncol. 2017;35(32):3638-3646. 3. Sledge GW, et al. MONARCH 2: Abemaciclib in combination with fulvestrant in women with HR+/HER2- advanced breast cancer. J Clin Oncol. 2017;35(25):2875-2884. 4. Dickler MN, et al. MONARCH 1: A phase II study of abemaciclib in patients with refractory HR+/HER2- metastatic breast cancer. Clin Cancer Res. 2018;24(21):5216-5224. 5. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 4.2023. 6. Spring LM, et al. Cyclin-dependent kinase 4/6 inhibitors in breast cancer: current status and future directions. Cancer Treat Rev. 2021;99:102269.