Purpose <p>Zolbetuximab, a monoclonal antibody targeting claudin 18.2 (CLDN18.2), is approved in combination with chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative, CLDN18.2-positive, unresectable, advanced or recurrent gastric cancer (in Japan) and in combination with fluoropyrimidine- and platinum-containing chemotherapy for first-line locally advanced unresectable or metastatic HER2-negative, CLDN18.2-positive gastric or gastroesophageal junction (G/GEJ) adenocarcinoma (in geographies including but not limited to the US, Europe, and China). Noncompartmental analysis (NCA) was previously used to evaluate the effect of zolbetuximab on pharmacokinetics (PK) of 5-fluorouracil (5-FU) and oxaliplatin; however, limitations of NCA confounded the results. This study utilized population pharmacokinetic (PopPK) analysis to address these limitations.</p> Methods <p>In Cohort 2 of the phase 2 ILUSTRO study (NCT03505320), patients with locally advanced unresectable or metastatic HER2-negative, CLDN18.2-positive G/GEJ adenocarcinoma received zolbetuximab with modified folinic acid, 5-FU, and oxaliplatin. PopPK models were developed to evaluate the impact of zolbetuximab on PK of 5-FU and oxaliplatin (including simultaneous analysis of free and total platinum).</p> Results <p>PK of 5-FU was adequately described by a 1-compartment model with zero-order input and first-order elimination. PK of free and total platinum was simultaneously described by a 3-compartment model with zero-order input, first-order elimination, and time-dependent free fraction. No impact of zolbetuximab on 5-FU PK or on systemic clearance or free fraction of oxaliplatin in plasma was observed. The effect of zolbetuximab on oxaliplatin distribution volume (12.3% decrease) was statistically significant but not considered clinically relevant.</p> Conclusion <p>PopPK analysis suggests no effect of zolbetuximab on 5-FU or oxaliplatin PK.</p>