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While inhibition of the receptor\u2013ligand interaction is key to the pharmacological activity of these drugs, it can be technically challenging to measure these intercellular interactions directly. Instead, target engagement (or receptor occupancy) is commonly measured, but may not always be an accurate predictor of receptor\u2013ligand inhibition, and can be misleading when used to inform clinical dose projections for this class of drugs. In this study, a mathematical model explicitly representing the intercellular receptor\u2013ligand interaction is used to compare dose prediction based on target engagement or receptor\u2013ligand inhibition for two checkpoint inhibitors, atezolizumab and magrolimab. For atezolizumab, there is little difference between target engagement and receptor\u2013ligand inhibition, but for magrolimab, the model predicts that receptor\u2013ligand inhibition is significantly less than target engagement. The key variables explaining the difference between these two drugs are the relative concentrations of the target receptors and their ligands. Drug\u2010target affinity and receptor\u2013ligand affinity can also have divergent effects on target engagement and inhibition. These results suggest that it is important to consider ligand\u2013receptor inhibition in addition to target engagement and demonstrate the impact of using modeling for efficacious dose estimation.<\/jats:p>","DOI":"10.1002\/psp4.13152","type":"journal-article","created":{"date-parts":[[2024,5,25]],"date-time":"2024-05-25T04:39:48Z","timestamp":1716611988000},"page":"919-925","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Comparison of dose selection based on target engagement versus inhibition of receptor\u2013ligand interaction for checkpoint inhibitors"],"prefix":"10.1002","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8942-7785","authenticated-orcid":false,"given":"Sarah A.","family":"Head","sequence":"first","affiliation":[{"name":"Certara  Concord Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1599-4453","authenticated-orcid":false,"given":"Carter","family":"Johnson","sequence":"additional","affiliation":[{"name":"Certara  Concord Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saheli","family":"Sarkar","sequence":"additional","affiliation":[{"name":"Certara  Concord Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Matteson","sequence":"additional","affiliation":[{"name":"Certara  Concord Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana H.","family":"Marcantonio","sequence":"additional","affiliation":[{"name":"Certara  Concord Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7728-2155","authenticated-orcid":false,"given":"Fei","family":"Hua","sequence":"additional","affiliation":[{"name":"Certara  Concord Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John M.","family":"Burke","sequence":"additional","affiliation":[{"name":"Certara  Concord Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3396-1874","authenticated-orcid":false,"given":"Joshua F.","family":"Apgar","sequence":"additional","affiliation":[{"name":"Certara  Concord Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7382-8461","authenticated-orcid":false,"given":"David","family":"Flowers","sequence":"additional","affiliation":[{"name":"Certara  Concord Massachusetts USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,5,24]]},"reference":[{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1002\/cyto.b.21355"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.18.02018"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/cpt.587"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-011-9232-2"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.4161\/mabs.23684"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2018.1462429"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2015.1136043"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0137345"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.864768"}],"container-title":["CPT: Pharmacometrics &amp; Systems Pharmacology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/psp4.13152","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,6,15]],"date-time":"2024-06-15T20:13:02Z","timestamp":1718482382000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/psp4.13152"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,5,24]]},"references-count":9,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2024,6]]}},"alternative-id":["10.1002\/psp4.13152"],"URL":"https:\/\/doi.org\/10.1002\/psp4.13152","archive":["Portico"],"relation":{},"ISSN":["2163-8306","2163-8306"],"issn-type":[{"value":"2163-8306","type":"print"},{"value":"2163-8306","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,5,24]]},"assertion":[{"value":"2023-12-24","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-04-10","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2024-05-24","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}