Zolbetuximab is a chimeric (mouse/human IgG1) monoclonal antibody directed against the tight junction molecule CLDN18.2. Nonclinical data suggest zolbetuximab binds selectively to cell lines transfected with CLDN18.2 or those that endogenously express CLDN18.2. Zolbetuximab depletes CLDN18.2-positive cells via antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). Cytotoxic medicinal products were shown to increase CLDN18.2 expression on human cancer cells and to improve zolbetuximab-induced ADCC and CDC activities.
Based on the exposure-response analyses of efficacy and safety in patients with locally advanced unresectable or metastatic HER2-negative gastric or GEJ adenocarcinoma whose tumours are CLDN18.2 positive, there are no anticipated clinically significant differences in efficacy or safety between zolbetuximab doses of 800/400 mg/m² every 2 weeks and 800/600 mg/m² every 3 weeks.
Following intravenous administration, zolbetuximab exhibited dose-proportional pharmacokinetics at doses ranging from 33 mg/m² to 1000 mg/m². When administered at 800/600 mg/m² every 3 weeks, steady state was achieved by 24 weeks with a mean (SD) Cmax and AUCtau at 453 (82) μg/mL and 4125 (1169) day•μg/mL, respectively, based on a population pharmacokinetic analysis. When administered at 800/400 mg/m² every 2 weeks, steady state is expected to be achieved by 22 weeks with a mean (SD) Cmax and AUCtau at 359 (68) μg/mL and 2758 (779) day•μg/mL, respectively, based on a population pharmacokinetics analysis.
The estimated mean steady state volume of distribution of zolbetuximab was 5.5 L.
Zolbetuximab is expected to be catabolised into small peptides and amino acids.
Zolbetuximab clearance (CL) decreased over time, with a maximal reduction from baseline values of 57.6% resulting in a population mean steady-state clearance (CLss) of 0.0117 L/h. The half-life of zolbetuximab ranged from 7.6 to 15.2 days during treatment.
Population pharmacokinetic analysis indicates that age [range: 22 to 83 years; 32.2% (230/714) were >65 years, 5.0% (36/714) were >75 years] did not have a clinically meaningful effect on the pharmacokinetics of zolbetuximab.
Based on the population pharmacokinetic analysis, no clinically significant differences in the pharmacokinetics of zolbetuximab were identified based on gender [62.3% male, 37.7% female] or race [50.1% Caucasian, 42.2% Asian, 4.2% Missing, 2.7% Others, and 0.8% Black].
Based on the population pharmacokinetic analysis using data from clinical studies in patients with gastric or GEJ adenocarcinoma, no clinically significant differences in the pharmacokinetics of zolbetuximab were identified in patients with mild (CrCL ≥60 to <90 mL/min; n=298) to moderate (CrCL ≥30 to <60 mL/min; n=109) renal impairment based on CrCL estimated by the Cockcroft-Gault formula. Zolbetuximab has only been evaluated in a limited number of patients with severe renal impairment (CrCL ≥15 to <30 mL/min; n=1). The effect of severe renal impairment on the pharmacokinetics of zolbetuximab is unknown.
Based on the population pharmacokinetic analysis using data from clinical studies in patients with gastric or GEJ adenocarcinoma, no clinically significant differences in the pharmacokinetics of zolbetuximab were identified in patients with mild hepatic impairment as measured by TB and AST (TB ≤ ULN and AST > ULN, or TB > 1 to 1.5 × ULN and any AST; n=108). Zolbetuximab has only been evaluated in a limited number of patients with moderate hepatic impairment (TB > 1.5 to 3 × ULN and any AST; n=4) and has not been evaluated in patients with severe hepatic impairment (TB > 3 to 10 × ULN and any AST). The effect of moderate or severe hepatic impairment on the pharmacokinetics of zolbetuximab is unknown.
No studies in animals have been performed to evaluate carcinogenicity or mutagenicity.
No toxicity or other zolbetuximab-related adverse effects on the cardiovascular, respiratory or central nervous systems was observed in mice administered zolbetuximab for 13 weeks at systemic exposures up to 7.0-fold the human exposure at the recommended dose of 600 mg/m² (based on AUC) or in cynomolgus monkeys administered zolbetuximab for 4 weeks at systemic exposures up to 6.1-fold the human exposure at the recommended dose of 600 mg/m² (based on AUC).
In an embryo-foetal development toxicity study, where zolbetuximab was administered to pregnant mice during the period of organogenesis at systemic exposures up to approximately 6.2-fold the human exposure at the recommended dose of 600 mg/m² (based on AUC), zolbetuximab crossed the placental barrier. The resulting concentration of zolbetuximab in foetal serum at Day 18 of gestation was higher than that in the maternal serum at Day 16 of gestation. Zolbetuximab did not result in any external or visceral foetal abnormalities (malformations or variations).
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