Pharmacological properties : תכונות פרמקולוגיות

Pharmacodynamic Properties

13.2 Pharmacodynamics
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 BRUKINSA on the QTc interval above the therapeutic exposure has not been evaluated.

Pharmacokinetic Properties

13.3 Pharmacokinetics
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 2,099 (42%) ng·h/mL following 160 mg twice daily and 1,917 (59%) ng·h/mL following 320 mg once daily. The geometric mean (%CV) zanubrutinib steady-state C max is 295 (55%) ng/mL following 160 mg twice daily and 537 (55%) ng/mL following 320 mg once daily.
Absorption
The median tmax 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 volume of distribution (Vz/F) of zanubrutinib is 537 (73%) 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 (t½) 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 128 (58%) 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 144 kg), or mild, moderate, or severe renal impairment (creatinine clearance [CLcr] ≥ 15 mL/min as estimated by Cockcroft-Gault). The effect of 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: Coadministration of multiple doses of CYP3A inhibitors increases zanubrutinib Cmax and AUC (Table 16).
Table 16:     Observed or Predicted Increase in Zanubrutinib Exposure After Co- Administration of CYP3A Inhibitors
Increase in              Increase in
Coadministered CYP3A Inhibitor
Zanubrutinib Cmax        Zanubrutinib AUC

Observed

Itraconazole (200 mg once daily)                        157%                     278% 
Predicted

Clarithromycin (250 mg twice daily)                     175%           183% 
Diltiazem (60 mg three times daily)                     151%           157% 
Erythromycin (500 mg four times daily)                  284%           317% 
Fluconazole (200 mg once daily)                         179%           177% 
Fluconazole (400 mg once daily)                         270%           284% 
CYP3A Inducers: Coadministration of multiple doses of rifampin (strong CYP3A inducer) decreased the zanubrutinib Cmax by 92% and AUC by 93%. Coadministration of multiple doses of rifabutin (moderate CYP3A inducer) decreased the zanubrutinib Cmax by 48% and AUC by 44%.
Coadministration of multiple doses of efavirenz (moderate CYP3A inducer) is predicted to decrease zanubrutinib Cmax by 58% and AUC by 60%.
CYP3A Substrates: Coadministration of multiple doses of zanubrutinib decreased midazolam (CYP3A substrate) Cmax by 30% and AUC by 47%.
CYP2C19 Substrates: Coadministration of multiple doses of zanubrutinib decreased omeprazole (CYP2C19 substrate) Cmax by 20% and AUC by 36%.
Other CYP Substrates: No clinically significant differences were observed with warfarin (CYP2C9 substrate) pharmacokinetics when Coadministered with zanubrutinib.
Transporter Systems: Coadministration of multiple doses of zanubrutinib increased digoxin (P- gp substrate) Cmax by 34% and AUC by 11%. No clinically significant differences in the pharmacokinetics of rosuvastatin (BCRP substrate) were observed when Coadministered with zanubrutinib.
Gastric Acid Reducing Agents: No clinically significant differences in zanubrutinib pharmacokinetics were observed when Coadministered with gastric acid reducing agents (proton pump inhibitors, H2-receptor antagonists).
In Vitro Studies
CYP Enzymes: Zanubrutinib is an inducer of CYP2B6 and CYP2C8.
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.