{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T13:10:18Z","timestamp":1789996218494,"version":"4.0.1"},"reference-count":36,"publisher":"Wiley","issue":"9","license":[{"start":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T00:00:00Z","timestamp":1788307200000},"content-version":"vor","delay-in-days":1,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T00:00:00Z","timestamp":1788220800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"funder":[{"DOI":"10.13039\/501100013076","name":"National Major Science and Technology Projects of China","doi-asserted-by":"publisher","award":["2020ZX09201022"],"award-info":[{"award-number":["2020ZX09201022"]}],"id":[{"id":"10.13039\/501100013076","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clinical Translational Sci"],"published-print":{"date-parts":[[2026,9]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>\n                    Rocbrutinib is a fourth\u2010generation Bruton's tyrosine kinase (BTK) inhibitor that covalently binds wild\u2010type BTK and non\u2010covalently engages the C481S mutant. Its pharmacokinetic (PK) characteristics in healthy Chinese subjects remain unclear. This study aimed to support maximum recommended starting dose (MRSD) selection and predict exposure of rocbrutinib in healthy Chinese subjects via an integrated model\u2010informed strategy. We determined key extrapolation parameters and preclinical PK in CD\u20101 mice and beagle dogs. Three approaches were employed to determine the MRSD: The no observed adverse effect level (NOAEL) dose method based on body surface area, the NOAEL exposure method based on a physiologically based pharmacokinetic (PBPK) model, and the minimum effective dose method based on a PBPK model. The PBPK model was developed and validated using preclinical and clinical PK data. Predicted MRSD values by the NOAEL dose method, the NOAEL exposure method, and the minimum effective dose method were 48.7, 9.8, and 10.5\u2009mg, respectively. Considering the lowest predicted value and available tablet strength, a starting dose of 12.5\u2009mg was selected. Predicted plasma concentration\u2010time profiles were consistent with those observed in animals and humans. The fold error for C\n                    <jats:sub>max<\/jats:sub>\n                    and AUC fell within the 0.5\u20132.0 range. The model further predicted brain tissue exposure across species. Moreover, the predicted brain BTK occupancy at 12.5\u2009mg was approximately 37% for wild\u2010type BTK and 6% for C481S mutant BTK. The PBPK model serves as a valuable tool for dose selection, PK prediction, and CNS target engagement evaluation, supporting the clinical development of rocbrutinib.\n                  <\/jats:p>","DOI":"10.1111\/cts.70715","type":"journal-article","created":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T07:49:16Z","timestamp":1788335356000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Physiologically Based Pharmacokinetic Modeling to Predict Human Starting Dose and Pharmacokinetics for Rocbrutinib"],"prefix":"10.1111","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8858-4896","authenticated-orcid":false,"given":"Lu","family":"Wang","sequence":"first","affiliation":[{"name":"Center of Clinical Pharmacology, the Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-7168-0364","authenticated-orcid":false,"given":"Dandan","family":"Yang","sequence":"additional","affiliation":[{"name":"Center of Clinical Pharmacology, the Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9854-4545","authenticated-orcid":false,"given":"Rong","family":"Shao","sequence":"additional","affiliation":[{"name":"Center of Clinical Pharmacology, the Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7981-0510","authenticated-orcid":false,"given":"Jinliang","family":"Chen","sequence":"additional","affiliation":[{"name":"Center of Clinical Pharmacology, the Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaodan","family":"Wang","sequence":"additional","affiliation":[{"name":"Center of Clinical Pharmacology, the Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zheng","family":"Wang","sequence":"additional","affiliation":[{"name":"Lupeng Pharmaceutical co. Ltd  GuangZhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2406-0959","authenticated-orcid":false,"given":"Bo","family":"Jiang","sequence":"additional","affiliation":[{"name":"Center of Clinical Pharmacology, the Second Affiliated Hospital Zhejiang University School of Medicine  Hangzhou China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,9,2]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1401483"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1129906"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1002\/art.40059"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1186\/s12974\u2010023\u201002997\u20102"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41582\u2010023\u201000800\u20107"},{"key":"e_1_2_9_7_1","doi-asserted-by":"publisher","DOI":"10.1186\/s13045\u2010026\u201001810\u2010w"},{"key":"e_1_2_9_8_1","unstructured":"U.S. Food and Drug Administration \u201cEstimating the Maximum Safe Starting Dose in Initial Clinical Trials for Therapeutics in Adult Healthy Volunteers \u201d(2005)."},{"key":"e_1_2_9_9_1","unstructured":"European Medicines Agency \u201cGuideline on Strategies to Identify and Mitigate Risks for First\u2010in\u2010Human and Early Clinical Trials With Investigational Medicinal Products \u201d(2017)."},{"key":"e_1_2_9_10_1","unstructured":"National Medical Products Administration \u201cGuidelines for Estimating the Maximum Recommended Starting Dose in the First Clinical Trial in Adult Healthy Volunteers 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