{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,29]],"date-time":"2026-08-29T15:21:58Z","timestamp":1788016918552,"version":"build-2784847793"},"reference-count":11,"publisher":"Wiley","issue":"10","license":[{"start":{"date-parts":[[2024,5,16]],"date-time":"2024-05-16T00:00:00Z","timestamp":1715817600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["accp1.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["The Journal of Clinical Pharma"],"published-print":{"date-parts":[[2024,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Belzutifan (Welireg, Merck &amp; Co., Inc., Rahway, NJ, USA) is an oral, potent hypoxia\u2010inducible factor\u20102\u03b1 inhibitor, recently approved in the United States for the treatment of von Hippel\u2013Lindau (VHL) disease\u2010associated renal cell carcinoma (RCC) and other VHL disease\u2010associated neoplasms. Safety and efficacy were investigated in two clinical studies: a Phase 1 dose escalation\/expansion study in solid tumors and RCC and a Phase 2 study in VHL\u2010RCC. A population pharmacokinetic model was used to estimate belzutifan exposures to facilitate exposure\u2013response (E\u2010R) analyses for efficacy and safety endpoints. Relationships between exposure and efficacy (overall response rate, disease control rate, progression\u2010free survival, best overall tumor size response, and other endpoints), safety outcomes (Grade \u22653 anemia, Grade \u22653 hypoxia, and time to first dose reduction\/dose interruption), and pharmacodynamic biomarkers (erythropoietin [EPO] and hemoglobin [Hgb]) were evaluated using various regression techniques and time\u2010to\u2010event analyses. Efficacy E\u2010R was generally flat with non\u2010significant positive trends with exposure. The safety E\u2010R analyses demonstrated a lack of relationship for Grade \u22653 hypoxia and a positive relationship for Grade \u22653 anemia, with incidences also significantly dependent on baseline Hgb. Exposure\u2010dependent reductions in EPO and Hgb were observed. Based on the cumulative benefit\u2013risk assessment in VHL disease\u2010associated neoplasms using E\u2010R, no a priori dose adjustment is recommended for any subpopulation. These analyses supported the benefit\u2013risk profile of belzutifan 120 mg once daily dosing in patients with VHL\u2010RCC for labeling and the overall development program.<\/jats:p>","DOI":"10.1002\/jcph.2459","type":"journal-article","created":{"date-parts":[[2024,5,16]],"date-time":"2024-05-16T07:13:49Z","timestamp":1715843629000},"page":"1246-1258","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Exposure\u2013Response Analyses for Belzutifan to Inform Dosing Considerations and Labeling"],"prefix":"10.1002","volume":"64","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0238-2252","authenticated-orcid":false,"given":"Dhananjay D.","family":"Marathe","sequence":"first","affiliation":[{"name":"Merck &amp; Co., Inc.  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