Zanubrutinib

Zanubrutinib is a small-molecule inhibitor of BTK. Zanubrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK activity. BTK is a signaling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signaling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion. In nonclinical studies, zanubrutinib inhibited malignant B-cell proliferation and reduced tumor growth.

BTK Occupancy in PBMCs and Lymph Nodes

The median steady-state BTK occupancy in peripheral blood mononuclear cells was maintained at 100% over 24 hours at a total daily dose of 320 mg in patients with B-cell malignancies. The median steady-state BTK occupancy in lymph nodes was 94% to 100% following the approved recommended dosage.

Cardiac Electrophysiology

At the approved recommended doses (160 mg twice daily or 320 mg once daily), there were no clinically relevant effects on the QTc interval. The effect of zanubrutinib on the QTc interval above the therapeutic exposure has not been evaluated.

Zanubrutinib maximum plasma concentration (C_max) and area under the plasma drug concentration over time curve (AUC) increase proportionally over a dosage range from 40 mg to 320 mg (0.13 to 1 time the recommended total daily dose). Limited systemic accumulation of zanubrutinib was observed following repeated administration.

The geometric mean (CV) zanubrutinib steady-state daily AUC is 2,295 (37) ng∙h/mL following 160 mg twice daily and 2,180 (41%) ng∙h/mL following 320 mg once daily. The geometric mean (CV) zanubrutinib steady-state C_max is 314 (46) ng/mL following 160 mg twice daily and 543 (51%) ng/mL following 320 mg once daily.

Absorption

The median t_max of zanubrutinib is 2 hours.

Effect of Food

No clinically significant differences in zanubrutinib AUC or C_max were observed following administration of a high-fat meal (approximately 1,000 calories with 50% of total caloric content from fat) in healthy subjects.

Distribution

The geometric mean (CV) apparent steady-state volume of distribution of zanubrutinib is 881 (95) L. The plasma protein binding of zanubrutinib is approximately 94% and the blood-to-plasma ratio is 0.7 to 0.8.

Elimination

The mean half-life (t_½) of zanubrutinib is approximately 2 to 4 hours following a single oral zanubrutinib dose of 160 mg or 320 mg. The geometric mean (CV) apparent oral clearance (CL/F) of zanubrutinib is 182 (37) L/h.

Metabolism

Zanubrutinib is primarily metabolized by cytochrome P450(CYP)3A.

Excretion

Following a single radiolabeled zanubrutinib dose of 320 mg to healthy subjects, approximately 87% of the dose was recovered in feces (38% unchanged) and 8% in urine (less than 1% unchanged).

Specific Populations

No clinically significant differences in the pharmacokinetics of zanubrutinib were observed based on age (19 to 90 years), sex, race (Asian, Caucasian, and Other), body weight (36 to 140 kg), or mild or moderate renal impairment (creatinine clearance [CLcr] ≥30 mL/min as estimated by Cockcroft-Gault). The effect of severe renal impairment (CLcr <30 mL/min) and dialysis on zanubrutinib pharmacokinetics is unknown.

Hepatic Impairment

The total AUC of zanubrutinib increased by 11% in subjects with mild hepatic impairment (Child-Pugh class A), by 21% in subjects with moderate hepatic impairment (Child-Pugh class B), and by 60% in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with normal liver function. The unbound AUC of zanubrutinib increased by 23% in subjects with mild hepatic impairment (Child-Pugh class A), by 43% in subjects with moderate hepatic impairment (Child-Pugh class B), and by 194% in subjects with severe hepatic impairment (Child-Pugh class C) relative to subjects with normal liver function.

Drug Interaction Studies

Clinical Studies and Model-Informed Approaches

CYP3A Inhibitors: Co-administration of multiple doses of CYP3A inhibitors increases zanubrutinib C_max and AUC (Table 6).

Table 6. Observed or Predicted Increase in Zanubrutinib Exposure After Co-Administration of CYP3A Inhibitors:

CYP3A Inducers: Co-administration of multiple doses of rifampin (strong CYP3A inducer) decreased the zanubrutinib C_max by 92% and AUC by 93%.

Co-administration of multiple doses of efavirenz (moderate CYP3A inducer) is predicted to decrease zanubrutinib C_max by 58% and AUC by 60%.

CYP3A Substrates: Co-administration of multiple doses of zanubrutinib decreased midazolam (CYP3A substrate) C_max by 30% and AUC by 47%.

CYP2C19 Substrates: Co-administration of multiple doses of zanubrutinib decreased omeprazole (CYP2C19 substrate) C_max by 20% and AUC by 36%.

Other CYP Substrates: No clinically significant differences were observed with warfarin (CYP2C9 substrate) pharmacokinetics or predicted with rosiglitazone (CYP2C8 substrate) pharmacokinetics when co-administered with zanubrutinib.

Transporter Systems: Co-administration of multiple doses of zanubrutinib increased digoxin (P-gp substrate) C_max by 34% and AUC by 11%. No clinically significant differences in the pharmacokinetics of rosuvastatin (BCRP substrate) were observed when co-administered with zanubrutinib.

Gastric Acid Reducing Agents: No clinically significant differences in zanubrutinib pharmacokinetics were observed when co-administered with gastric acid reducing agents (proton pump inhibitors, H2-receptor antagonists).

In Vitro Studies

CYP Enzymes: Zanubrutinib is an inducer of CYP2B6.

Transporter Systems: Zanubrutinib is likely to be a substrate of P-gp. Zanubrutinib is not a substrate or inhibitor of OAT1, OAT3, OCT2, OATP1B1, or OATP1B3.