Introduction
Brukinsa (zanubrutinib) is a novel, small molecule Bruton's tyrosine kinase (BTK) inhibitor developed by BeiGene. It received FDA approval in November 2019 for the treatment of certain B-cell malignancies. As a second-generation BTK inhibitor, Brukinsa offers improved selectivity and potentially fewer off-target effects compared to earlier agents in its class.
Mechanism of Action
Brukinsa covalently binds to the cysteine 481 residue in the BTK active site, irreversibly inhibiting BTK enzymatic activity. BTK is a crucial signaling molecule in the B-cell receptor (BCR) pathway, which regulates B-cell proliferation, differentiation, and survival. By inhibiting BTK, Brukinsa disrupts BCR-mediated signaling, leading to reduced malignant B-cell survival and proliferation. The drug demonstrates higher selectivity for BTK compared to first-generation inhibitors, with reduced inhibition of other kinases including ITK, EGFR, and TEC.
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 orally once daily Administration: Can be taken with or without food Dose modifications: Recommended for severe hematologic toxicities and certain non-hematologic toxicities Special populations:- Renal impairment: No dose adjustment needed for mild to moderate impairment
- Hepatic impairment: Not recommended in severe hepatic impairment (Child-Pugh C)
- Elderly: No dose adjustment required based on age alone
Pharmacokinetics
Absorption: Rapidly absorbed with median Tmax of 2 hours Distribution: Volume of distribution approximately 100 L; 94% protein bound Metabolism: Primarily via CYP3A4; also undergoes hydrolysis and reduction Elimination: Half-life of 2-4 hours; fecal excretion (mostly as metabolites) is primary route Bioavailability: Reduced by 37% with high-fat mealContraindications
- Hypersensitivity to zanubrutinib or any component of the formulation
- Concurrent use with strong CYP3A inducers
- Severe hepatic impairment (Child-Pugh C)
Warnings and Precautions
Hemorrhage: Serious fatal hemorrhagic events reported; monitor for bleeding Infections: Serious bacterial, fungal, and viral infections may occur Cytopenias: Grade 3-4 neutropenia, thrombocytopenia, and anemia reported Cardiac arrhythmias: Atrial fibrillation and flutter reported in up to 3.7% of patients Second primary malignancies: Other malignancies reported including skin cancers Embryo-fetal toxicity: Can cause fetal harm based on mechanism of actionDrug Interactions
Strong CYP3A inhibitors: Increase zanubrutinib exposure; reduce dose to 80 mg twice daily Strong CYP3A inducers: Contraindicated due to significantly decreased exposure Moderate CYP3A inducers: Avoid concomitant use if possible Anticoagulants/antiplatelets: Increased bleeding risk with warfarin, DOACs, and antiplatelet agents P-gp substrates: May increase concentrations of narrow therapeutic index P-gp substratesAdverse Effects
Most common (≥20%): Neutropenia (42%), thrombocytopenia (33%), anemia (29%), upper respiratory tract infection (28%), rash (23%), musculoskeletal pain (22%), diarrhea (20%) Serious adverse reactions: Pneumonia (9%), hemorrhage (5%), neutropenia (5%), anemia (3%) Other notable effects: Hypertension, second primary malignancies, atrial fibrillation/flutterMonitoring Parameters
Baseline: CBC with differential, hepatic function, renal function, ECG if cardiac history During treatment: CBC with differential monthly for first 3 months, then periodically; monitor for signs of bleeding and infection; blood pressure monitoring; signs/symptoms of atrial fibrillation Periodic: Hepatic and renal function tests; skin examination for secondary malignanciesPatient Education
- Take exactly as prescribed; do not change dose or stop without medical advice
- Report any signs of bleeding (unusual bruising, blood in urine/stool)
- Monitor for fever, chills, or other signs of infection
- Be aware of potential cardiac symptoms (palpitations, dizziness, shortness of breath)
- Use effective contraception during treatment and for at least 1 week after final dose
- Inform all healthcare providers about Brukinsa use before any procedures
- Store at room temperature in original container
References
1. FDA Prescribing Information: Brukinsa (zanubrutinib). November 2019. 2. Tam CS, et al. Zanubrutinib for the treatment of patients with Waldenström macroglobulinemia: 3-year follow-up. Blood. 2020;135(19):155-166. 3. Song Y, et al. Pharmacokinetics and pharmacodynamics of zanubrutinib, a selective Bruton's tyrosine kinase inhibitor. Clin Pharmacokinet. 2020;59(6):739-749. 4. Trotman J, et al. Zanubrutinib for the treatment of patients with relapsed/refractory mantle cell lymphoma. Blood Adv. 2021;5(12):2577-2585. 5. NCCN Guidelines: B-Cell Lymphomas. Version 3.2022. 6. ClinicalTrials.gov: Multiple phase 1/2 and phase 3 trials of zanubrutinib.