Zenocutuzumab is a bispecific antibody that binds to the extracellular domains of HER2 and HER3 expressed on the surface of cells, including tumor cells, inhibiting HER2:HER3 dimerization and preventing NRG1 binding to HER3. Zenocutuzumab decreased cell proliferation and signaling through the phosphoinositide 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) pathway. In addition, zenocutuzumab mediates antibody-dependent cellular cytotoxicity (ADCC). Zenocutuzumab showed antitumor activity in mouse models of NRG1 fusion-positive lung and pancreatic cancers.
The exposure-response relationship and time-course of pharmacodynamic response for zenocutuzumab have not been fully characterized.
Zenocutuzumab pharmacokinetic parameters are expressed as mean unless otherwise specified. Zenocutuzumab exposure increases proportionally over a dose range from 480 mg (0.6 times the approved recommended dosage) to 900 mg (1.2 times the approved recommended dosage). The median time to steady state of zenocutuzumab concentrations is 8 weeks and the median accumulation ratio is 1.6-fold at the approved recommended dosage.
Zenocutuzumab volume of distribution is 6 L (CV 18%).
The steady state zenocutuzumab half-life is 8 days (SD ±1.3 days) with a clearance of 22 mL/h (CV 37%).
Zenocutuzumab is expected to be metabolized into small peptides by catabolic pathways.
No clinically significant differences in the pharmacokinetics of zenocutuzumab were observed based on age (22 to 88 years), sex, race [White or Asian], body weight (38 to 126 kg), albumin level (20 to 49 g/L), mild or moderate renal impairment (creatinine clearance (CLcr) 30 to 89 mL/min), and mild hepatic impairment (total bilirubin >1 to 1.5 times ULN or AST > ULN).
The pharmacokinetics of zenocutuzumab in patients with moderate to severe hepatic impairment (total bilirubin >1.5 to 3 times ULN with any AST) or severe renal impairment (CLcr <30 mL/min) is unknown
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