{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T19:48:29Z","timestamp":1784576909087,"version":"3.55.0"},"reference-count":22,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2020,7,24]],"date-time":"2020-07-24T00:00:00Z","timestamp":1595548800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2020,9]]},"abstract":"<jats:p>Targeted biological therapies may achieve maximal therapeutic efficacy at doses below the maximum tolerated dose (MTD); therefore, the search for the MTD in clinical studies may not be ideal for these agents. Emactuzumab is an investigational monoclonal antibody that binds to and inhibits the activation of the cell surface colony\u2010stimulating factor\u20101 receptor. Here, we show how modeling target\u2010mediated drug disposition coupled with pharmacodynamic end points was used to optimize the dose of emactuzumab without defining an MTD. The model could be used to recommend doses across different disease indications. The approach recommended an optimal biological dose of emactuzumab for dosing every 2\u00a0weeks (q2w) \u2265\u00a0900\u00a0mg, approximately three\u2010fold lower than the highest dose tested clinically. The model predicted that emactuzumab doses \u2265\u00a0900\u00a0mg q2w would achieve target saturation in excess of 90% over the entire dosing cycle. Subsequently, a dose of 1,000\u00a0mg q2w was used in the extension phase of a phase I study of emactuzumab in patients with advanced solid tumors or diffuse\u2010type tenosynovial giant cell tumor. Clinical data from this study were consistent with model predictions. The model was also used to predict the optimum dose of emactuzumab for use with dosing every 3\u00a0weeks, enabling dosing flexibility with respect to comedications. In summary, this work demonstrates the value of quantitative clinical pharmacology approaches to dose selection in oncology as opposed to traditional MTD methods.<\/jats:p>","DOI":"10.1002\/cpt.1964","type":"journal-article","created":{"date-parts":[[2020,6,23]],"date-time":"2020-06-23T23:48:00Z","timestamp":1592956080000},"page":"616-624","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["PK\/PD Mediated Dose Optimization of Emactuzumab, a CSF1R Inhibitor, in Patients With Advanced Solid Tumors and Diffuse\u2010Type Tenosynovial Giant Cell Tumor"],"prefix":"10.1111","volume":"108","author":[{"given":"Kevin","family":"Smart","sequence":"first","affiliation":[{"name":"Roche Innovation Center Welwyn Welwyn Garden City UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ann\u2010Marie","family":"Br\u00f6ske","sequence":"additional","affiliation":[{"name":"Roche Innovation Center Munich Penzberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"R\u00fcttinger","sequence":"additional","affiliation":[{"name":"Roche Innovation Center Munich Penzberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Mueller","sequence":"additional","affiliation":[{"name":"Roche Innovation Center Munich Penzberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Phipps","sequence":"additional","affiliation":[{"name":"Roche Innovation Center Welwyn Welwyn Garden City UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antje\u2010Christine","family":"Walz","sequence":"additional","affiliation":[{"name":"Roche Innovation Center Basel Basel Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carola","family":"Ries","sequence":"additional","affiliation":[{"name":"Roche Innovation Center Munich Penzberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monika","family":"Baehner","sequence":"additional","affiliation":[{"name":"Roche Innovation Center Munich Penzberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Cannarile","sequence":"additional","affiliation":[{"name":"Roche Innovation Center Munich Penzberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgina","family":"Meneses\u2010Lorente","sequence":"additional","affiliation":[{"name":"Roche Innovation Center Welwyn Welwyn Garden City UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2020,7,24]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccr.2014.05.016"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.tcb.2004.09.016"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-013-0367-7"},{"key":"e_1_2_10_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.1027"},{"key":"e_1_2_10_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/1479-5876-9-216"},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0507321103"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(15)00132-1"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1093\/annonc\/mdz163"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2014.153"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1517\/17460441.2.2.185"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2006.07.4658"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-005-0074-7"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2014.00174"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.drudis.2007.10.002"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-010-9156-2"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-014-9360-6"},{"key":"e_1_2_10_17_1","unstructured":"US Food and Drug Administration.FDA's Critical Path Initiative(2012) <http:\/\/www.fdagov\/ScienceResearch\/SpecialTopics\/CriticalPathInitiative\/ucm076689.htm>."},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcp.2005.12.041"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1023\/A:1014414520282"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1007\/s10928-014-9372-2"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1124\/jpet.112.191999"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/pds.744"}],"container-title":["Clinical Pharmacology &amp; 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