{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T06:41:13Z","timestamp":1784875273060,"version":"3.55.0"},"reference-count":12,"publisher":"Wiley","issue":"7","license":[{"start":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T00:00:00Z","timestamp":1751414400000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2025,7,1]],"date-time":"2025-07-01T00:00:00Z","timestamp":1751328000000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2025,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Zolbetuximab is a chimeric (mouse\/human) monoclonal antibody directed against the tight junction protein claudin 18.2, which is highly expressed in gastric\/gastroesophageal junction (G\/GEJ) and pancreatic adenocarcinoma. We report a population pharmacokinetic (PK) and exposure\u2010response (E\u2010R) analysis of zolbetuximab in patients with locally advanced unresectable or metastatic G\/GEJ adenocarcinoma. A population PK model for zolbetuximab was developed using data from eight clinical studies to generate exposure metrics for safety\/efficacy E\u2010R analyses of three trials. A two\u2010compartment model with zero\u2010order input and time\u2010dependent clearance adequately characterized zolbetuximab serum concentration\u2010time data. Estimated mean clearance at baseline, steady\u2010state clearance, steady\u2010state volume of distribution, and elimination half\u2010life were 0.0276\u2009L\/h, 0.0117\u2009L\/h, 5.53\u2009L, and 7.56\u201315.2\u2009days, respectively. Time required for trough concentration to reach steady state was 24\u2009weeks. Mild hepatic or mild\/moderate renal impairment did not alter zolbetuximab PK. Gastrectomy increased average zolbetuximab concentration (30%), trough concentration (first dose, 114%; steady state, 50%), and area under the concentration\u2010time curve (26%\u201334%), but maximum concentrations were similar (gastrectomy vs. no gastrectomy) and no clinical relevance is anticipated. Multivariable Cox proportional hazard modeling indicated statistically significant relationships between average zolbetuximab concentration and progression\u2010free survival and overall survival (both\n                    <jats:italic>p<\/jats:italic>\n                    \u2009&lt;\u20090.0001) after controlling for other relevant covariates. Maximum concentration after the first dose was significantly associated with gastrointestinal adverse events and infusion\u2010related reactions. The phase 3 zolbetuximab regimen of 800\/600\u2009mg\/m\n                    <jats:sup>2<\/jats:sup>\n                    every 3\u2009weeks was supported by efficacy\/safety data; an alternative regimen of 800\/400\u2009mg\/m\n                    <jats:sup>2<\/jats:sup>\n                    every 2\u2009weeks was predicted to have similar efficacy\/safety.\n                  <\/jats:p>","DOI":"10.1111\/cts.70280","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T23:44:27Z","timestamp":1751499867000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Population\n                    <scp>PK<\/scp>\n                    and Exposure\u2010Response Analyses of Zolbetuximab in Patients With Locally Advanced Unresectable or Metastatic G\/\n                    <scp>GEJ<\/scp>\n                    Adenocarcinoma"],"prefix":"10.1111","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-7527-1897","authenticated-orcid":false,"given":"Akihiro","family":"Yamada","sequence":"first","affiliation":[{"name":"Astellas Pharma, Inc.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masato","family":"Takeuchi","sequence":"additional","affiliation":[{"name":"Astellas Pharma, Inc.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kanji","family":"Komatsu","sequence":"additional","affiliation":[{"name":"Astellas Pharma, Inc.  Tokyo Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter L.","family":"Bonate","sequence":"additional","affiliation":[{"name":"Astellas Pharma Global Development, Inc.  Northbrook Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Srinivasu","family":"Poondru","sequence":"additional","affiliation":[{"name":"Astellas Pharma Global Development, Inc.  Northbrook Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianning","family":"Yang","sequence":"additional","affiliation":[{"name":"Astellas Pharma Global Development, Inc.  Northbrook Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2025,7,2]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v28.i12.1187"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fonc.2023.1258347"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.prp.2024.155145"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-08-1547"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(23)00620-7"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-023-02465-7"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz199"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.annonc.2021.02.005"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-23-0204"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-019-00816-7"},{"key":"e_1_2_10_12_1","unstructured":"\u201cICH Harmonised Guideline Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management \u201d2019 accessed September 4 2024 https:\/\/database.ich.org\/sites\/default\/files\/Q12_Guideline_Step4_2019_1119.pdf."},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2007.11.0304"}],"container-title":["Clinical and Translational Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70280","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1111\/cts.70280","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1111\/cts.70280","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,3,23]],"date-time":"2026-03-23T11:46:16Z","timestamp":1774266376000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1111\/cts.70280"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,7]]},"references-count":12,"journal-issue":{"issue":"7","published-print":{"date-parts":[[2025,7]]}},"alternative-id":["10.1111\/cts.70280"],"URL":"https:\/\/doi.org\/10.1111\/cts.70280","archive":["Portico"],"relation":{},"ISSN":["1752-8054","1752-8062"],"issn-type":[{"value":"1752-8054","type":"print"},{"value":"1752-8062","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,7]]},"assertion":[{"value":"2025-01-22","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-06-06","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-07-02","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e70280"}}