Ζanidatamab

Zanidatamab is a bispecific HER2-directed antibody that binds to two extracellular sites on HER2. Binding of zanidatamab with HER2 results in internalization leading to a reduction of the receptor on the tumor cell surface. Zanidatamab induces complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). These mechanisms result in tumor growth inhibition and cell death in vitro and in vivo.

Zanidatamab exposure-response relationships and the time course of the pharmacodynamic response are unknown.

Cardiac Electrophysiology

A mean increase in the QTc interval >20 ms was not observed at the recommended approved dosage.

Zanidatamab PK parameters are presented as means (percent coefficient of variation) following administration of zanidatamab 20 mg/kg every 2 weeks after the 7^th or later dose unless otherwise indicated.

Zanidatamab maximum concentration (C_max) is 600 (22.2) µg/mL, the lowest measured concentration (C_trough) is 178 (29.6) µg/mL, and total systemic exposure (AUC_0-336h) is 3,976 (22.5) days*µg/mL following administration of zanidatamab. The C_max of zanidatamab is dose proportional and the total systemic exposure (AUC_0-inf) of zanidatamab is greater than dose proportional with increasing doses. The mean C_trough accumulation ratio of zanidatamab is approximately 2.4.

Distribution

The volume of distribution of zanidatamab is approximately 7.5 (33) L based on the population pharmacokinetic analysis.

Elimination

The estimated half-life (t_1/2) of zanidatamab is approximately 21 days with an associated clearance (CL) of 0.012 L/h (27.9) based on the population pharmacokinetic analysis.

Metabolism

Zanidatamab is expected to be metabolized into small peptides by catabolic pathways.

Specific Populations

No clinically significant differences in the pharmacokinetics of zanidatamab-hrii were observed based on age (24 to 88 years), sex, race (White and Asian), mild and moderate renal impairment (eGFR 30 to 89 mL/min estimated using the CKD‑EPI), mild hepatic impairment (total bilirubin ≤ upper limit of normal (ULN) and AST > ULN or total bilirubin between 1 and 1.5 times ULN and any AST), or body weight (35 kg to 128 kg).

The effect of severe renal impairment (eGFR 15 to 29 mL/min), end-stage renal disease (eGFR <15 mL/min) with or without hemodialysis, and moderate (total bilirubin >1.5 to ≤3 ULN and any AST) or severe (total bilirubin >3 ULN and any AST) hepatic impairment on the pharmacokinetics of zanidatamab is unknown.