Zanubrutinib CAS No. 1691249-45-2

Uses

• Indications:

  • Treatment of relapsed/refractory mantle cell lymphoma (MCL) in adults who have received at least one prior therapy.

  • Treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) in adults.

  • Treatment of Waldenström’s macroglobulinemia (WM) in adults.

  • Treatment of relapsed/refractory marginal zone lymphoma (MZL) in adults who have received at least one anti-CD20-based regimen.

  • Treatment of relapsed/refractory follicular lymphoma (FL) in adults who have received at least two prior systemic therapies.

• Off-Label Uses:

  • Treatment of patients with CLL/SLL who are intolerant of ibrutinib or acalabrutinib.

  • Treatment of patients with CLL/SLL harboring del(17p) and/or TP53 mutations.

Mechanism of Action

• Zanubrutinib is a potent and selective next-generation BTK inhibitor.

• It inhibits BTK by forming a covalent bond with cysteine 481 residue in the ATP-binding pocket of BTK.

• This binding specificity is common with other BTK inhibitors.

• By blocking the BCR signaling pathway, zanubrutinib inhibits the proliferation, trafficking, chemotaxis, and adhesion of malignant B cells, ultimately leading to reduced tumor size.

Pharmacokinetics

• Absorption:

  • Following oral administration of zanubrutinib 160 mg twice daily and 320 mg once daily, the mean steady-state concentrations were 2,295 (37%) ng·h/mL and 2,180 (41%) ng·h/mL, respectively.

  • The mean Cmax (%CV) was 314 (46%) ng/mL following 160 mg twice daily and 543 (51%) ng/mL following 320 mg once daily.

  • The Cmax and AUC of zanubrutinib increase in a dose-proportional manner, with minimal systemic accumulation after repeated dosing.

  • The median Tmax is 2 hours.

• Distribution:

  • The geometric mean (%CV) apparent steady-state Vd is 881 (95%) L.

  • The blood-to-plasma ratio is about 0.7 to 0.8.

• Metabolism:

  • Zanubrutinib is predominantly metabolized by CYP3A4.

  • Its metabolites have not been characterized.

• Excretion:

  • Following oral administration of 320 mg radiolabeled zanubrutinib, approximately 87% of the dose was excreted in the feces and about 8% of the dose was recovered in the urine.

  • Less than 1% of the recovered drug comprised unchanged parent drug.

• Half-Life:

  • The mean half-life is approximately 2 to 4 hours following administration of a single oral dose of 160 mg or 320 mg of zanubrutinib.

Properties

• Molecular Formula: C₂₇H₂₉N₅O₃

• Molecular Weight: 463.55 g/mol

• IUPAC Name: 1-[(3R)-3-[4-[(5R)-5-(4-phenoxyphenyl)-4,5-dihydro-1,2-oxazol-3-yl]piperidin-1-yl]piperidin-1-yl]-2-propen-1-one

• CAS Number: 1691249-45-2

• InChI Key: RNOAOAWBMHREKO-QFIPXVFZSA-N

• SMILES: C=CC(=O)N1CCC(CC1)[C@@H]2CCNC3=C(C(=NN23)C4=CC=C(C=C4)OC5=CC=CC=C5)C(=O)N

• Computed Descriptors:

  • XLogP3: 3.5

  • Hydrogen Bond Donor Count: 2

  • Hydrogen Bond Acceptor Count: 5

  • Rotatable Bond Count: 6

  • Exact Mass: 471.22703980 Da

  • Monoisotopic Mass: 471.22703980 Da

  • Topological Polar Surface Area: 102 Ų

  • Heavy Atom Count: 35

  • Formal Charge: 0

  • Complexity: 756

  • Isotope Atom Count: 0

  • Defined Atom Stereocenter Count: 1

  • Undefined Atom Stereocenter Count: 0

  • Defined Bond Stereocenter Count: 0

  • Undefined Bond Stereocenter Count: 0

  • Covalently-Bonded Unit Count: 1

Safety and Toxicity

• Adverse Events:

  • The most common treatment-emergent adverse events (TEAEs) in patients treated with zanubrutinib include fatigue, COVID-19, contusion, diarrhea, arthralgia, and cough.

  • Grade ≥3 TEAEs include neutropenia, pneumonia, COVID-19, and hypertension.

  • Atrial fibrillation of any grade occurred in 6% of patients, with 3% experiencing grade ≥3 atrial fibrillation.

  • Hemorrhage of any grade occurred in 44% of patients, with 1 patient experiencing grade ≥3 hemorrhage.

  • Treatment-emergent hypertension of any grade occurred in 20% of patients, with 6% experiencing grade ≥3 hypertension.

• Intolerance AEs:

  • In patients intolerant of ibrutinib or acalabrutinib, zanubrutinib showed low recurrence rates of intolerance AEs.

  • Only 40% of ibrutinib-intolerance AEs and 28% of acalabrutinib-intolerance AEs recurred with zanubrutinib.

  • Recurrent AEs were mostly lower grade, and no AEs recurred at a higher grade with zanubrutinib.

    Regulatory Approvals

  • FDA Approvals:

    • Accelerated approval for the treatment of relapsed/refractory mantle cell lymphoma (MCL) in November 2019.

    • Accelerated approval for the treatment of Waldenström’s macroglobulinemia in August 2021.

    • Accelerated approval for the treatment of relapsed/refractory marginal zone lymphoma (MZL) in September 2021.

    • Full approval for the treatment of chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) in October 2022.

  • EMA Approvals:

    • Recommended for marketing authorization for the treatment of chronic lymphocytic leukemia in October 2022.

Product Documents

• Safety Data Sheet (SDS)
• Certificate of Analysis
• Product Brochure
• Technical Data Sheet