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General Description:

Zanubrutinib, identified by CAS number 1691249-45-2, is a notable compound with significant therapeutic applications. Zanubrutinib is a novel Bruton's tyrosine kinase (BTK) inhibitor used for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. Mantle cell lymphoma is an aggressive mature B-cell non-Hodgkin lymphoma that is associated with early relapse, poor clinical outcomes, and long-term survival. BTK is an enzyme that plays a role in oncogenic signalling pathways, where it promotes the survival and proliferation of malignant B cells. Compared to the first-generation BTK inhibitor , zanubrutinib displays higher potency and selectivity for BTK with fewer off-target effects. Due to this enhanced selectivity towards BTK, zanubrutinib belongs to the second-generation BTK inhibitor drug group that also includes , which was approved by the FDA in 2017. Zanubrutinib was granted accelerated approval by the FDA in November 2019 based on clinical trial results that demonstrated an 84% overall response rate from zanubrutinib therapy in patients with MCL, which measures the proportion of patients in a trial whose tumour is entirely or partially destroyed by a drug. It is currently marketed under the trade name BRUKINSA™ and is available as oral capsules. In August 2021, the FDA granted accelerated approval to zanubrutinib for the treatment of adults with Waldenström’s macroglobulinemia. This indication is valid in the US, Europe, and Canada. In September 2021, zanubrutinib was granted another accelerated approval for the treatment of relapsed or refractory marginal zone lymphoma who have received at least one anti-CD20-based regimen. In October 2022, the EMA's Committee for Medicinal Products for Human Use (CHMP) recommended zanubrutinib be granted marketing authorization for the treatment of chronic lymphocytic leukaemia.

Indications:

This drug is primarily indicated for: Zanubrutinib is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy. It is used to treat Waldenström’s macroglobulinemia in adults. Zanubrutinib is also indicated for the treatment of relapsed or refractory marginal zone lymphoma (MZL) in adults who have received at least one anti-CD20-based regimen. Its use in specific medical scenarios underscores its importance in the therapeutic landscape.

Metabolism:

Zanubrutinib undergoes metabolic processing primarily in: Zanubrutinib is predominantly metabolized by CYP3A4. Its metabolites have not been characterized. This metabolic pathway ensures efficient processing of the drug, helping to minimize potential toxicity and side effects.

Absorption:

The absorption characteristics of Zanubrutinib are crucial for its therapeutic efficacy: Following oral administration of zanubrutinib 160 mg twice daily and 320 mg once daily, the mean (%CV) zanubrutinib 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 and there is minimal systemic accumulation after repeated dosing. The median Tmax is 2 hours. The drug's ability to rapidly penetrate into cells ensures quick onset of action.

Half-life:

The half-life of Zanubrutinib is an important consideration for its dosing schedule: Following administration of a single oral dose of 160 mg or 320 mg of zanubrutinib, the mean half-life is approximately 2 to 4 hours. This determines the duration of action and helps in formulating effective dosing regimens.

Protein Binding:

Zanubrutinib exhibits a strong affinity for binding with plasma proteins: The plasma protein binding of zanubrutinib is approximately 94%. This property plays a key role in the drug's pharmacokinetics and distribution within the body.

Route of Elimination:

The elimination of Zanubrutinib from the body primarily occurs through: Following oral administration of 320 mg radiolabelled zanubrutinib, approximately 87% of the dose was excreted in the feces and about 8% of the dose was recovered in the urine, where less than 1% of the recovered drug comprised of unchanged parent drug. Understanding this pathway is essential for assessing potential drug accumulation and toxicity risks.

Volume of Distribution:

Zanubrutinib is distributed throughout the body with a volume of distribution of: The geometric mean (%CV) apparent steady-state Vd is 881 (95%) L. The blood-to­ plasma ratio is about 0.7 to 0.8. This metric indicates how extensively the drug permeates into body tissues.

Clearance:

The clearance rate of Zanubrutinib is a critical factor in determining its safe and effective dosage: The mean (%CV) apparent oral clearance (CL/F) of zanubrutinib is 182 (37%) L/h. It reflects the efficiency with which the drug is removed from the systemic circulation.

Pharmacodynamics:

Zanubrutinib exerts its therapeutic effects through: Zanubrutinib is an immunomodulating agent that decreases the survival of malignant B cells. It inhibits BTK by binding to its active site. It works to inhibit the proliferation and survival of malignant B cells to reduce the tumour size in mantle cell lymphoma. The drug's ability to modulate various physiological processes underscores its efficacy in treating specific conditions.

Mechanism of Action:

Zanubrutinib functions by: Bruton's tyrosine kinase (BTK) is a non-receptor kinase and a signalling molecule for the B cell receptors expressed on the peripheral B cell surface. The BCR signalling pathway plays a crucial role in normal B-cell development but also the proliferation and survival of malignant B cells in many B cell malignancies, including mantle-cell lymphoma (MCL). Once activated by upstream Src-family kinases, BTK phosphorylates phospholipase-Cγ (PLCγ), leading to Ca2+ mobilization and activation of NF-κB and MAP kinase pathways. These downstream cascades promote the expression of genes involved in B cell proliferation and survival. The BCR signalling pathway also induces the anti-apoptotic protein Bcl-xL and regulates the integrin α4β1 (VLA-4)-mediated adhesion of B cells to vascular cell adhesion molecule-1 (VCAM-1) and fibronectin via BTK. Apart from the direct downstream signal transduction pathway of B cells, BTK is also involved in chemokine receptor, Toll-like receptor (TLR) and Fc receptor signalling pathways. Zanubrutinib inhibits BTK by forming a covalent bond with cysteine 481 residue in the adenosine triphosphate (ATP)–binding pocket of BTK, which is the enzyme's active site. This binding specificity is commonly seen with other BTK inhibitors. Due to this binding profile, zanubrutinib may also bind with varying affinities to related and unrelated ATP-binding kinases that possess a cysteine residue at this position. By blocking the BCR signalling pathway, zanubrutinib inhibits the proliferation, trafficking, chemotaxis, and adhesion of malignant B cells, ultimately leading to reduced tumour size. Zanubrutinib was also shown to downregulate programmed death-ligand 1 (PD-1) expression and cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) on CD4+ T cells. This mechanism highlights the drug's role in inhibiting or promoting specific biological pathways, contributing to its therapeutic effects.

Toxicity:

Classification:

Zanubrutinib belongs to the class of organic compounds known as diphenylethers. These are aromatic compounds containing two benzene rings linked to each other through an ether group, classified under the direct parent group Diphenylethers. This compound is a part of the Organic compounds, falling under the Benzenoids superclass, and categorized within the Benzene and substituted derivatives class, specifically within the Diphenylethers subclass.

Categories:

Zanubrutinib is categorized under the following therapeutic classes: Antineoplastic Agents, Antineoplastic and Immunomodulating Agents, Bruton's tyrosine kinase (BTK) inhibitors, Bruton's Tyrosine Kinase Inhibitors, Cytochrome P-450 CYP2B6 Inducers, Cytochrome P-450 CYP2B6 Inducers (strength unknown), Cytochrome P-450 CYP2B6 Substrates, Cytochrome P-450 CYP2B6 Substrates with a Narrow Therapeutic Index, Cytochrome P-450 CYP3A Substrates, Cytochrome P-450 CYP3A4 Substrates, Cytochrome P-450 CYP3A4 Substrates with a Narrow Therapeutic Index, Cytochrome P-450 Enzyme Inducers, Cytochrome P-450 Substrates, Enzyme Inhibitors, Hematologic Agents, Kinase Inhibitor, Narrow Therapeutic Index Drugs, P-glycoprotein substrates, P-glycoprotein substrates with a Narrow Therapeutic Index, Protein Kinase Inhibitors, Teratogens. These classifications highlight the drug's diverse therapeutic applications and its importance in treating various conditions.