{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,8]],"date-time":"2026-10-08T02:02:59Z","timestamp":1791424979493,"version":"4.3.3"},"reference-count":32,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2024,12,9]],"date-time":"2024-12-09T00:00:00Z","timestamp":1733702400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["CPT Pharmacom &amp; Syst Pharma"],"published-print":{"date-parts":[[2025,3]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>In oncology drug development, measuring drug concentrations at the tumor site and at the targeted receptor remains an ongoing challenge. Positron emission tomography (PET)\u2010imaging is a promising noninvasive method to quantify intratumor exposure of a radiolabeled drug (biodistribution data) and target saturation by treatment doses in\u00a0vivo. Here, we present the development and application of a minimal physiologically\u2010based pharmacokinetic (mPBPK) modeling approach to integrate biodistribution data in a quantitative platform to characterize and predict intratumor exposure and receptor occupancy (RO) of BI 754111, an IgG\u2010based anti\u2010lymphocyte\u2010activation gene 3 (LAG\u20103) monoclonal antibody (mAb). Specifically, calibration and qualification of the predictions were performed using <jats:sup>89<\/jats:sup>Zr\u2010labeled BI 754111 biodistribution data, that is, PET\u2010derived intratumor drug concentration data, tumor\u2010to\u2010plasma ratios, and data from Patlak analyses. The model predictions were refined iteratively by the inclusion of additional biological processes into the model structure and the use of sensitivity analyses to assess the impact of model assumptions and parameter uncertainty on the predictions and model robustness. The developed mPBPK model allowed an adequate description of observed tumor radioactivity concentrations and tumor\u2010to\u2010plasma ratios leading to subsequent adequate prediction of LAG\u20103 RO at different dose levels. In the future, the developed model could be used as a platform for the prediction and analysis of biodistribution data for other mAbs and may ultimately support dose optimization by identifying dosages resulting in saturated RO.<\/jats:p>","DOI":"10.1002\/psp4.13285","type":"journal-article","created":{"date-parts":[[2024,12,10]],"date-time":"2024-12-10T07:40:04Z","timestamp":1733816404000},"page":"460-473","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["A minimal physiologically\u2010based pharmacokinetic modeling platform to predict intratumor exposure and receptor occupancy of an anti\u2010<scp>LAG<\/scp>\u20103 monoclonal antibody"],"prefix":"10.1002","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5485-607X","authenticated-orcid":false,"given":"Robin","family":"Michelet","sequence":"first","affiliation":[{"name":"qPharmetra LLC  Berlin Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Klas","family":"Petersson","sequence":"additional","affiliation":[{"name":"qPharmetra LLC  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc C.","family":"Huisman","sequence":"additional","affiliation":[{"name":"Department of Radiology and Nuclear Medicine Amsterdam UMC, Vrije Universiteit Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C. Willemien","family":"Menke\u2010van der Houven van Oordt","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Amsterdam UMC, Vrije Universiteit Amsterdam  Amsterdam The Netherlands"},{"name":"Imaging and Biomarkers Cancer Center Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7581-5277","authenticated-orcid":false,"given":"Iris H. C.","family":"Miedema","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology Amsterdam UMC, Vrije Universiteit Amsterdam  Amsterdam The Netherlands"},{"name":"Imaging and Biomarkers Cancer Center Amsterdam  Amsterdam The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Thiele","sequence":"additional","affiliation":[{"name":"Boehringer Ingelheim Pharma GmbH &amp; Co. 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KG  Ingelheim am Rhein Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2024,12,9]]},"reference":[{"key":"e_1_2_13_2_1","unstructured":"US Food and Drug Administration.Project Optimus: Reforming the dose optimization and dose selection paradigm in oncology. 2023.https:\/\/www.fda.gov\/about\u2010fda\/oncology\u2010center\u2010excellence\/project\u2010optimus. 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