Molecular mass: 471.561 g/mol
Zanubrutinib is an inhibitor of Bruton’s tyrosine kinase (BTK). Zanubrutinib forms a covalent bond with a cysteine residue in the BTK active site, leading to inhibition of BTK activity. BTK is a signalling molecule of the B-cell antigen receptor (BCR) and cytokine receptor pathways. In B-cells, BTK signalling results in activation of pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.
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 recommended dose.
At the recommended doses (320 mg once daily or 160 mg twice daily), there were no clinically relevant effects on the QTc interval. At a single dose 1.5 times the maximum recommended dose (480 mg), zanubrutinib did not prolong the QT interval to any clinically relevant extent (i.e., ≥10 msec).
Zanubrutinib maximum plasma concentration (Cmax) and area under the plasma drug concentration over time curve (AUC) increase proportionally over a dose 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 for one week.
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 Cmax is 299 (56) ng/mL following 160 mg twice daily and 533 (55%) ng/mL following 320 mg once daily.
The median tmax of zanubrutinib is 2 hours. No clinically significant differences in zanubrutinib AUC or Cmax were observed following administration of a high-fat meal (approximately 1,000 calories with 50% of total caloric content from fat) in healthy subjects.
The geometric mean (CV) apparent steady-state volume of distribution of zanubrutinib during the terminal phase (Vz/F) was 522 L (71). The plasma protein binding of zanubrutinib is approximately 94% and the blood-to-plasma ratio was 0.7-0.8.
Zanubrutinib is primarily metabolized by cytochrome P450(CYP)3A.
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 during the terminal phase was 128 (61) L/h. Following a single radiolabelled zanubrutinib dose of 320 mg to healthy subjects, approximately 87% of the dose was recovered in faeces (38% unchanged) and 8% in urine (less than 1% unchanged).
Age (19 to 90 years; mean age 65±12.5) had no clinically meaningful effect on zanubrutinib pharmacokinetics based on population PK analysis (N=1291).
No pharmacokinetic studies were performed with zanubrutinib in patients under 18 years of age.
Gender (872 males and 419 females) had no clinically meaningful effect on zanubrutinib pharmacokinetics based on population PK analysis.
Race (964 White, 237 Asian, 30 Black, and 25 categorized as Other) had no clinically meaningful effect on zanubrutinib pharmacokinetics based on population PK analysis.
Body weight (36 to 149 kg, mean weight 76.5±16.9 kg) had no clinically meaningful effect on zanubrutinib pharmacokinetics based on population PK analysis (N=1291).
Zanubrutinib undergoes minimal renal elimination. Based on population PK analysis, mild and moderate renal impairment (CrCl ≥30 mL/min as estimated by Cockcroft-Gault equation) had no influence on the exposure of zanubrutinib. The analysis was based on 362 patients with normal renal function, 523 with mild renal impairment, 303 with moderate renal impairment, 11 with severe renal impairment, and one with ESRD. The effects of severe renal impairment (CrCl <30 mL/min) and dialysis on zanubrutinib pharmacokinetics is unknown.
The total AUC of zanubrutinib increased by 11% in subjects with mild hepatic impairment (ChildPugh 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. A significant correlation was observed between the Child-Pugh score, baseline serum albumin, baseline serum bilirubin and baseline prothrombin time with unbound zanubrutinib AUC.
Zanubrutinib is a weak inducer of CYP2B6 and CYP2C8. Zanubrutinib is not an inducer of CYP1A2.
Zanubrutinib is likely to be a substrate of P-gp. Zanubrutinib is not a substrate or inhibitor of OAT1, OAT3, OCT2, OATP1B1, or OATP1B3.
An in vitro study showed that the potential pharmacodynamic interaction between zanubrutinib and rituximab is low and zanubrutinib is unlikely to interfere with the anti-CD20 antibody-induced antibody-dependent cellular cytotoxicity (ADCC) effect.
In vitro, ex vivo, and animal studies showed that zanubrutinib had no or minimal effects on platelet activation, glycoprotein expression, and thrombus formation.
The general toxicologic profiles of zanubrutinib were characterized orally in Sprague-Dawley rats for up to 6-month treatment and in beagle dogs for up to 9-month treatment.
In rat repeat dose studies up to 6-month treatment, test article related mortality was noted at the dose of 1,000 mg/kg/day (81x clinical AUC) with histopathologic findings in the gastrointestinal tract. Other findings were mainly noted in the pancreas (atrophy, fibroplasia, haemorrhage, and/or inflammatory cell infiltration) at the doses ≥30 mg/kg/day (3x clinical AUC), in the skin around the nose/mouth/eyes (inflammatory cell infiltration, erosion/ulcer) from the dose of 300 mg/kg/day (16x clinical AUC), and in the lung (presence of macrophages in the alveolar) at the dose of 300 mg/kg/day. All these findings were fully or partially reversed after a 6-week recovery except for the pancreatic findings which were not considered clinically relevant.
In dog repeat dose studies up to 9-month treatment, test article related findings were mainly noted in the gastrointestinal tract (soft/watery/mucoid stool), skin (rash, red discoloration, and thickened/ scaling), and in the mesenteric, mandibular, and gut associated lymph nodes and spleen (lymphoid depletion or erythrophagocytosis) at the doses from 10 mg/kg/day (3x clinical AUC) to 100 mg/kg/day (18x clinical AUC). All these findings were fully or partially reversed after a 6-week recovery.
Carcinogenicity studies have not been conducted with zanubrutinib.
Zanubrutinib was not mutagenic in a bacterial mutagenicity (Ames) assay, was not clastogenic in a chromosome aberration assay in mammalian (Chinese hamster ovary) cells, nor was it clastogenic in an in vivo bone marrow micronucleus assay in rats.
A combined male and female fertility and early embryonic development study was conducted in rats at oral zanubrutinib doses of 30, 100 and 300 mg/kg/day. No effect on male or female fertility was noted but at the highest dose tested, morphological abnormalities in sperm and increased postimplantation loss were noted. The dose of 100 mg/kg/day is approximately 13-fold higher than the human therapeutic exposure.
Embryo-foetal development toxicity studies were conducted in both rats and rabbits. Zanubrutinib was administered orally to pregnant rats during the period of organogenesis at doses of 30, 75, and 150 mg/kg/day. Malformations in the heart (2- or 3-chambered hearts with the incidence of 0.3%-1.5%) were noted at all dose levels in the absence of maternal toxicity. The dose of 30 mg/kg/day is approximately 5-fold higher than the human therapeutic exposure.
Administration of zanubrutinib to pregnant rabbits during the period of organogenesis at 30, 70, and 150 mg/kg/day resulted in post-implantation loss at the highest dose. The dose of 70 mg/kg is approximately 25-fold higher than the human therapeutic exposure and was associated with maternal toxicity.
In a pre- and post-natal developmental toxicity study, zanubrutinib was administered orally to rats at doses of 30, 75, and 150 mg/kg/day from implantation through weaning. The offspring from the middle and high dose groups had decreased body weights preweaning, and all dose groups had adverse ocular findings (e.g., cataract, protruding eye). The dose of 30 mg/kg/day is approximately 5-fold higher than the human therapeutic exposure.
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