Nubeqa
Nubeqa
Generic Name
Nubeqa
Mechanism
Abemaciclib targets CDK4/6, enzymes that phosphorylate the retinoblastoma (Rb) protein, thereby promoting progression from the G1 to the S phase of the cell cycle.
• Selective inhibition of CDK4/6 leads to hypophosphorylated Rb, which sequesters E2F transcription factors and arrests tumor cells in G1.
• By coupling with anti‑estrogen therapy, abemaciclib prevents epithelial‑to‑mesenchymal transition and delays acquired resistance.
Pharmacokinetics
- Absorption: Oral; ~36 % bioavailability. Peak plasma concentration (Tmax) ~1 h post‑dose.
- Distribution: Highly protein‑bound (~97 %). Volume of distribution ~6 L/kg.
- Metabolism: Primarily CYP3A4/5 mediated; minor role for CYP2D6.
- Elimination: CYP3A4 metabolites (~80 %) + renal excretion (~8 %).
- Half‑life: ~18 h; steady state achieved by day 4 of continuous dosing.
- Drug interactions: Concurrent strong CYP3A4 inhibitors (e.g., ketoconazole) or inducers (e.g., rifampin) can substantially alter exposure.
Indications
- HR⁺ / HER2⁻ metastatic or advanced breast cancer in combination with letrozole, exemestane, or fulvestrant (postmenopausal or post‑ovariectomy).
- Approved for adjuvant setting (early‑stage disease) in combination with endocrine therapy to reduce recurrence risk.
Contraindications
- Contraindications: Known hypersensitivity to abemaciclib or any excipients.
- Warnings:
- Diarrhea: Common; may be life‑threatening; requires prompt treatment.
- Neutropenia & leukopenia: Monitor CBC; dose modifications required.
- Infections: Increased risk; treat promptly.
- Pregnancy: Category X – potential teratogenicity. Avoid use in pregnancy; use effective contraception.
- QT prolongation: Rare; avoid concomitant QT‑prolonging agents.
Dosing
- Typical dose: 150 mg twice daily (morning & evening) orally, continuous dosing for two 21‑day cycles followed by 14 days off (21 + 7 + 7 + 7 + 7 + 7 + 7 + 7 + 7 + 7).
- Start‑up: Begin first 7 days at 150 mg BID; after 7 days, reduce to 150 mg QD if diarrhea or neutropenia occurs.
- Route: Oral.
- Food effect: Food does not affect absorption.
Adverse Effects
- Common
- Diarrhea (≈55 %)
- Nausea/vomiting (≈20 %)
- Fatigue (≈25 %)
- Rash (≈12 %)
- Anemia (≈10 %)
- Serious
- Severe neutropenia (≈4 %) → infection, febrile neutropenia.
- Sepsis / septic shock (rare).
- Lymphocytopenia (≈3 %) → opportunistic infections.
- Hepatotoxicity (rare) – monitor LFTs.
Monitoring
| Parameter | Frequency | Notes |
| CBC with differential | Every 2 weeks first 3 months, then every 4 weeks | Alert for neutropenia > grade 3 |
| Serum creatinine & electrolytes | Every 4 weeks | Diarrhea can impair renal function |
| LFTs | Every 4 weeks | Signs of hepatotoxicity |
| Electrolytes & albumin | Every 4 weeks | Monitor dehydration, hyponatremia |
| QT interval (ECG) | Baseline, then every 3 months if on other QT‑prolonging drugs | Avoid if QTc > 500 ms |
Clinical Pearls
- Diarrhea is the most dose‑limiting toxicity; pre‑emptive loperamide (≤ 4 mg QID) and oral rehydration solutions are crucial.
- Dose reductions vs. drug holidays: A 25 % dose reduction (150 mg QD) often suffices; resort to 7‑day break only if toxicities persist.
- Combination therapy: The most common regimen is letrozole + abemaciclib; add a CDK4/6 inhibitor early to extend progression‑free survival by ~6 months.
- Renal impairment (CrCl < 30 mL/min): Dose adjustment not formally studied; use with caution, close monitoring.
- Drug interactions: Strong CYP3A4 inhibitors (ketoconazole, itraconazole) should be avoided; strong CYP3A4 inducers (rifampin) necessitate dose increases or alternative therapy.
- Pregnancy testing: Essential prior to initiation; maintain effective contraception for 3 months post‑therapy.
*Note*: All dosing and monitoring guidelines are derived from FDA‑approved labeling and pivotal phase‑III trials (MONARCH 1, MONARCH 2, MONARCH 3).