{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T12:15:12Z","timestamp":1788437712230,"version":"build-2803163510"},"reference-count":209,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immune checkpoint inhibitors (ICIs), particularly programmed cell death protein-1 (PD-1) antibodies, exhibit substantial interpatient variability in both efficacy and immune-related adverse events (irAEs). Conventional exposure-response (E-R) paradigms are often insufficient to capture these dynamics, limiting their utility for individualized immunotherapy.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To critically re-evaluate the E-R relationship of Sintilimab in advanced gastric cancer (AGC) by integrating pharmacokinetics (PK), host- and tumor-related determinants, and multidimensional biomarkers.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This review examines and critically discusses published PK and E-R data on Sintilimab and other PD-1\/PD-L1 inhibitors, with a focus on time-dependent clearance, target-mediated drug disposition (TMDD), and inter-individual variability. Clinical and mechanistic studies linking exposure metrics, clearance (CL), efficacy, and irAEs were critically analyzed, and key covariates influencing drug exposure were identified.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Time-dependent CL confounds traditional exposure metrics. CL may serve as a surrogate marker reflecting host physiology, tumor burden, and systemic inflammation. Multi-level biomarkers modulate the translation of drug exposure into therapeutic efficacy and toxicity. Conceptually, the exposure\u2013efficacy relationship of PD-1 inhibitors is more likely to be saturable or plateau-like after sufficient target occupancy, whereas higher exposure levels may increase the risk of irAEs without substantially enhancing efficacy beyond target saturation. Thus, the concept of an optimal benefit-risk range, rather than a simple \u201chigher-exposure-is-better\u201d strategy, is more appropriate for describing the E-R relationship of PD-1 inhibitors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We conceptualize a dynamic exposure\u2013response framework for Sintilimab in AGC by integrating time-dependent clearance, disease-state confounding, biomarker modulation, therapeutic drug monitoring (TDM), and model-informed precision dosing (MIPD). This framework provides a conceptual basis for optimizing individualized therapy and improving the benefit-risk balance in patients with AGC.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1875485","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T11:29:21Z","timestamp":1788434961000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Exposure\u2013response relationship of sintilimab in advanced gastric cancer: insights from time-dependent pharmacokinetics and biomarker integration for precision immunotherapy"],"prefix":"10.3389","volume":"17","author":[{"given":"Jingyi","family":"Zhou","sequence":"first","affiliation":[{"name":"Department of Oncology, Zhongda Hospital, Medical School of Southeast University","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingzhi","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Zhongda Hospital, Medical School of Southeast University","place":["Nanjing, Jiangsu, China"]},{"name":"Department of Radiotherapy Oncology, The First People\u2019s Hospital of Yancheng, Affiliated Hospital of Medical School, Nanjing University","place":["Yancheng, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Oncology, Zhongda Hospital, Medical School of Southeast University","place":["Nanjing, Jiangsu, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1939","DOI":"10.1007\/s00262-020-02797-0","article-title":"Genetic determinants of immune-related adverse events in patients with melanoma receiving immune checkpoint inhibitors","volume":"70","author":"Abdel-Wahab","year":"2021","journal-title":"Cancer Immunol. 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