Introduction
Zanubrutinib is a second-generation Bruton's tyrosine kinase (BTK) inhibitor approved for the treatment of various B-cell malignancies. As a highly selective, small molecule inhibitor, it represents an important advancement in targeted therapy for hematologic cancers, offering improved specificity and potentially fewer off-target effects compared to first-generation BTK inhibitors.
Mechanism of Action
Zanubrutinib covalently binds to cysteine 481 in the BTK active site, irreversibly inhibiting BTK enzymatic activity. BTK is a crucial component of the B-cell receptor (BCR) signaling pathway, which promotes B-cell proliferation, survival, and migration. By inhibiting BTK, zanubrutinib disrupts BCR signaling, leading to inhibited malignant B-cell proliferation and survival, and promotes apoptosis through multiple downstream pathways including NF-κB and MAPK signaling.
Indications
- Mantle cell lymphoma (MCL) in adults who have received at least one prior therapy
- Waldenström's macroglobulinemia (WM) in adults
- Chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adults
- Marginal zone lymphoma (MZL) in adults who have received at least one anti-CD20-based therapy
Dosage and Administration
Standard dosing: 160 mg orally twice daily or 320 mg once daily
Administration: Administer with or without food
Dose modifications: Recommended for severe hematologic toxicities, cardiac arrhythmias, and severe non-hematologic toxicities
Special populations:
- Renal impairment: No dosage adjustment necessary for mild to moderate impairment
- Hepatic impairment: Not recommended in patients with severe hepatic impairment
- Elderly: No dosage adjustment required based on age alone
Pharmacokinetics
Absorption: Rapidly absorbed with median Tmax of 2 hours
Distribution: Volume of distribution approximately 110 L; 94% protein-bound
Metabolism: Primarily via CYP3A4; minor contributions from CYP2C8 and CYP2C19
Elimination: Half-life of 2-4 hours; primarily fecal excretion (87%) with minor renal excretion (8%)
Bioavailability: Not significantly affected by food
Contraindications
- Hypersensitivity to zanubrutinib or any component of the formulation
- Concurrent use with strong CYP3A inducers
- Severe hepatic impairment (Child-Pugh Class C)
Warnings and Precautions
Hemorrhage: Serious and fatal hemorrhagic events reported; monitor for signs of bleeding
Infections: Serious bacterial, fungal, and viral infections may occur
Cytopenias: Grade 3 or 4 neutropenia, thrombocytopenia, and anemia reported
Cardiac arrhythmias: Atrial fibrillation and flutter reported; monitor symptoms
Second primary malignancies: Other malignancies, including skin cancers, reported
Embryo-fetal toxicity: Can cause fetal harm; advise women of reproductive potential
Drug Interactions
Strong CYP3A inhibitors: Increase zanubrutinib exposure; avoid concomitant use or reduce dose
Strong CYP3A inducers: Decrease zanubrutinib exposure; contraindicated
Moderate CYP3A inhibitors: May increase exposure; monitor for toxicity
Anticoagulants/antiplatelets: Increased bleeding risk; monitor closely
P-gp substrates: May increase concentrations of narrow therapeutic index P-gp substrates
Adverse Effects
Very common (≥10%): Neutropenia, thrombocytopenia, anemia, upper respiratory tract infection, rash, bruising, diarrhea, cough
Common (1-10%): Pneumonia, hemorrhage, hypertension, musculoskeletal pain, fatigue, nausea
Serious adverse reactions: Hemorrhage, infections, atrial fibrillation/flutter, cytopenias, second primary malignancies
Monitoring Parameters
Baseline: CBC with differential, hepatic function, renal function, ECG if indicated
During treatment: CBC with differential (monthly), signs/symptoms of infection, bleeding manifestations, cardiac symptoms
Periodic monitoring: Hepatic and renal function, skin examinations for secondary malignancies
Therapeutic drug monitoring: Not routinely required
Patient Education
- Take exactly as prescribed; do not change dose or stop without medical advice
- Report signs of bleeding, infection, irregular heartbeat, or unusual bruising
- Use effective contraception during treatment and for ≥1 week after last dose
- Inform all healthcare providers about zanubrutinib use before any procedures
- Be aware of potential drug interactions, particularly with certain antibiotics and antifungals
- Store at room temperature in original container
References
1. FDA Prescribing Information: Brukinsa (zanubrutinib)
2. Tam CS, et al. Zanubrutinib for the treatment of patients with Waldenström macroglobulinemia:
3-year follow-up. Blood. 2020;135(19):1555-1563. 3. Song Y, et al. Pharmacokinetics and pharmacodynamics of zanubrutinib, a selective Bruton tyrosine kinase inhibitor. Clin Pharmacokinet. 2020;59(6):727-737.
4. NCCN Guidelines: B-Cell Lymphomas (Version 4.2023)
5. Trotman J, et al. The BTK inhibitor zanubrutinib demonstrates superior efficacy and safety in patients with relapsed/refractory chronic lymphocytic leukemia. Clin Cancer Res. 2021;27(15):4173-4185.
6. ClinicalTrials.gov: Multiple trials including ASPEN (NCT03053440), SEQUOIA (NCT03336333)
