Zanubrutinib

Uses

Zanubrutinib is a kinase inhibitor used to treat mantle cell lymphoma, a type of B-cell non-Hodgkin lymphoma, in adults who previously received therapy.

Zanubrutinib is indicated for the treatment of adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy.

Zanubrutinib is also used to associated treatment for these conditions: Mantle Cell Lymphoma (MCL)

How Zanubrutinib works

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.

Toxicity

There is limited data on zanubrutinib overdose.

Food Interaction

• Avoid grapefruit products. Grapefruit inhibits CYP3A metabolism, which may increase the serum concentration of zanubrutinib. Dose adjustment may be necessary if coadministered.
• Avoid St. John's Wort. This herb induces CYP3A metabolism and may reduce serum levels of zanubrutinib.
• Take with a full glass of water.
• Take with or without food. Food does not significantly affect drug concentrations.

[Major] GENERALLY AVOID: Grapefruit juice may increase the plasma concentrations of zanubrutinib.

The proposed mechanism is inhibition of CYP450 3A4-mediated first-pass metabolism in the gut wall by certain compounds present in grapefruit.

Inhibition of hepatic CYP450 3A4 may also contribute.

The interaction has not been studied with grapefruit juice, but has been reported for other CYP450 3A4 inhibitors.

When zanubrutinib was administered with the potent CYP450 3A4 inhibitor itraconazole (200 mg once daily) in clinical study subjects, zanubrutinib peak plasma concentration (Cmax) and systemic exposure (AUC) increased by 157% and 278%, respectively.

Data derived from pharmacokinetic modeling have also been reported for several additional CYP450 3A4 inhibitors.

For example, the potent CYP450 3A4 inhibitor clarithromycin (250 mg twice daily) is predicted to increase zanubrutinib Cmax and AUC by 175% and 183%, respectively.

The moderate CYP450 3A4 inhibitor diltiazem (60 mg three times daily) is predicted to increase zanubrutinib Cmax and AUC by 151% and 157%, respectively.

Another moderate CYP450 3A4 inhibitor, erythromycin (500 mg four times daily), is predicted to increase zanubrutinib Cmax and AUC by 284% and 317%, respectively.

Likewise, fluconazole 200 mg once daily is predicted to increase zanubrutinib Cmax and AUC by 179% and 177%, respectively, while fluconazole 400 mg once daily is predicted to increase zanubrutinib Cmax and AUC by 270% and 284%, respectively.

In general, the effect of grapefruit juice is concentration-, dose- and preparation-dependent, and can vary widely among brands.

Certain preparations of grapefruit juice (e.g., high dose, double strength) have sometimes demonstrated potent inhibition of CYP450 3A4, while other preparations (e.g., low dose, single strength) have typically demonstrated moderate inhibition.

Increased zanubrutinib exposure may potentiate the risk of toxicities such as hemorrhage, infection, cytopenias, malignancies, and atrial fibrillation or flutter.

Food does not affect the oral bioavailability of zanubrutinib.

No clinically significant differences in zanubrutinib Cmax or AUC were observed following administration of a high-fat meal (approximately 1000 calories; 50% from fat) in healthy subjects.

MANAGEMENT: Zanubrutinib may be administered with or without food.

Patients should avoid consumption of grapefruit and grapefruit juice during treatment with zanubrutinib.

Zanubrutinib Hypertension interaction

[Moderate] Atrial fibrillation and atrial flutter have occurred in patients treated with zanubrutinib monotherapy.

Care should be exercised when using this agent in patients with cardiac risk factors, hypertension, and acute infections as they may be at increased risk of cardiac arrhythmias.

It is recommended to monitor for signs and symptoms of atrial fibrillation and atrial flutter and manage as appropriate.

Zanubrutinib Drug Interaction

Major: naproxen, nirmatrelvir / ritonavirModerate: suvorexant, duloxetineUnknown: amoxicillin / clavulanate, sulfamethoxazole / trimethoprim, metronidazole, penicillin v potassium, famotidine, acetaminophen / oxycodone, fluoride topical

Zanubrutinib Disease Interaction

Moderate: arrhythmias, bleeding, cytopenias, hepatic impairment, infections, renal impairment

Volume of 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.

Elimination Route

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.

Half Life

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.

Clearance

The mean (%CV) apparent oral clearance (CL/F) of zanubrutinib is 182 (37%) L/h.

Elimination Route

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.

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