Verzenio
Verzenio
Generic Name
Verzenio
Mechanism
- Selective inhibition of CDK4/6: Blocks phosphorylation of the retinoblastoma protein (Rb), arresting the G1→S transition in the cell cycle.
- Antiproliferative activity in HR+ breast cancer cells.
- Synergistic with endocrine therapy (e.g., aromatase inhibitors, fulvestrant) by preventing re‑entry into the cell cycle.
- Minimal off‑target kinase activity, yielding a favorable safety profile compared to first‑generation CDK4/6 inhibitors.
Pharmacokinetics
| Parameter | Key Points |
| Absorption | Oral tablet, ~80 % bioavailability; peak plasma conc. 4–6 h post‑dose. |
| Distribution | Extensive distribution; volume of distribution ~522 L. Highly protein‑bound (~94 %). |
| Metabolism | Predominantly via CYP3A4; minor contributions from UGT1A3/1A9. |
| Elimination | Mainly fecal (≈55 %) with renal excretion (~11 %). Half‑life ~18 h; supports BID dosing. |
| Drug‑Drug Interactions | Strong CYP3A4 inhibitors (e.g., ketoconazole) ↑ exposure; strong inducers (e.g., rifampin) ↓ exposure. Dose adjustment not routinely required for moderate/moderate interactions, but monitor. |
Indications
- HR+ / HER2‑negative metastatic breast cancer in the following settings:
- First‑line: with an aromatase inhibitor (AI) *or* with fulvestrant.
- Second‑line: after progression on AI (≥6 mo) or fulvestrant.
- Third‑line: after progression on CDK4/6 inhibitor *palbociclib* or *ribociclib*.
- Combination with endocrine therapy is preferred; monotherapy optional in specific patient scenarios.
Contraindications
| Category | Rationale |
| Contraindications | *None* per FDA labeling, but caution in patients with... |
| Warnings |
• Myelosuppression: neutropenia, anemia, thrombocytopenia. • Diarrhea: up to 60 % incidence (often dose‑dependent). • Lymphopenia: risk of opportunistic infections. • Fatigue: common. • Drug interactions: potent CYP3A4 inhibitors/inducers. |
| Precautions |
• Pregnancy: animal studies show fetal toxicity; use effective contraception. • Hepatic impairment: mild–moderate may increase exposure; monitor. • Renal impairment: increase in plasma concentration; adjust monitoring. |
Dosing
- Standard regimen:
- 150 mg orally, BID (continuous 7 days on / 21 days off *or* 21 days on / 7 days off cycle).
- Start after a 2 week regimen review; transition to either dosing schedule based on tolerability.
- Titration: If ≥Grade 3 diarrhea or hematologic toxicity, temporarily hold or reduce dose to 100 mg BID; re‑initiate once symptoms subside.
- Patient instructions: Take with food; maintain consistent daily timing.
Adverse Effects
| Severity | Adverse Effect |
| Common (≥10 %) |
• Diarrhea (most frequent) • Nausea, vomiting • Fatigue • Anemia, neutropenia (low‑grade) • Hypertension (mild) |
| Serious (≥1 %) |
• Severe neutropenia (risk of infection) • Grade 4 anemia • Severe diarrhea requiring IV fluids or hospitalization • Opportunistic infections (e.g., Pneumocystis jirovecii) • Rare arterial thromboembolism |
Monitoring
- Baseline: CBC (with diff), CMP, liver enzymes, bilirubin, urinalysis.
- On therapy:
- CBC: every 2 weeks first 2 months, then every 4 weeks.
- CMP: Every 4 weeks or as clinically indicated.
- Monitor for diarrhea: treat proactively with loperamide; consider antidiarrheal prophylaxis.
- Vaccinations: Update pneumococcal and influenza before initiating therapy.
- QTc interval: not routinely required unless using other QT‑prolonging drugs.
Clinical Pearls
- Diarrhea Prophylaxis: Initiate loperamide 1‑2 mg PO BID immediately upon first episode; consider prophylaxis for high‑risk patients (e.g., prior GI toxicity).
- Dose‑Adjusted Cycling: The 21 days on / 7 days off schedule can mitigate hematologic toxicity while maintaining efficacy; useful for frail elderly or those with pre‑existing cytopenias.
- Pregnancy and Lactation: Strongly contraindicated; use effective contraception for ≥6 months after discontinuation due to potential teratogenicity.
- Drug interactions: Mitigate with CYP3A4 modulators; hold abemaciclib for >2 days after a strong CYP3A4 inhibitor, and resume 10 days after a strong inducer.
- Immunotherapy Overlap: Co‑administration with immune checkpoint inhibitors requires caution; monitor for overlapping toxicities (e.g., colitis).
- Prior CDK4/6 Inhibitor Exposure: Patients progressing on palbociclib or ribociclib still benefit from abemaciclib owing to distinct resistance mechanisms; no cross‑resistance reported.
- Monitoring for Lymphopenia: A CBC with differential every 6 weeks is recommended for patients ≥65 yrs or with comorbidities that predispose to infections.
- Patient Counseling: Emphasize the importance of reporting new fevers, abdominal pain, or persistent diarrhea; early intervention prevents dose interruptions.
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