{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T12:29:32Z","timestamp":1788352172832,"version":"build-2803163510"},"reference-count":35,"publisher":"Wiley","issue":"12","license":[{"start":{"date-parts":[[2025,7,27]],"date-time":"2025-07-27T00:00:00Z","timestamp":1753574400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Br J Clin Pharmacol"],"published-print":{"date-parts":[[2025,12]]},"abstract":"<jats:sec>\n                    <jats:title>Aims<\/jats:title>\n                    <jats:p>Casdatifan is an orally bioavailable small\u2010molecule hypoxia\u2010inducible factor\u20102\u03b1 (HIF\u20102\u03b1) inhibitor currently in development for treating patients with clear cell renal cell carcinomas. The aim of this study was to characterize the pharmacokinetics (PK), pharmacodynamics and safety of casdatifan in healthy participants.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This first\u2010in\u2010human study (NCT05117554) investigating casdatifan in 70 healthy participants consisted of 3 parts: a double\u2010blind, randomized, placebo\u2010controlled single ascending dose (3\u2013100\u2009mg) part; a multiple ascending dose (15\u201350\u2009mg once daily) part; and an open\u2010label, fixed sequence, 2\u2010period, drug\u2013drug interaction part to evaluate the effect of multiple doses of casdatifan on the single\u2010dose PK of midazolam.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>In healthy participants, casdatifan plasma exposure increased dose proportionally over a single dose of 3\u2013100\u2009mg and multiple daily doses of 15\u201350\u2009mg. The mean half\u2010life of casdatifan was approximately 24\u2009h, and PK parameters did not change over time. Dose\u2010 and concentration\u2010dependent reduction, ranging from 41 to 85%, in erythropoietin (a pharmacodynamic biomarker for peripheral, nontumour, HIF\u20102\u03b1 inhibition) was observed after single and multiple doses, consistent with HIF\u20102\u03b1 pathway inhibition. Results from the midazolam drug\u2013drug interaction part indicated that casdatifan was a weak CYP3A4 inducer at the tested dose. Urine PK data showed that approximately 30% of the overall casdatifan clearance appears to be via renal clearance.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>Casdatifan, after single and multiple dosing in healthy participants, was safe and tolerable. Linear PK was associated with a mean maximum erythropoietin reduction of 85% following a single dose and multiple doses of casdatifan, demonstrating a promising exposure\u2013biological activity profile.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/bcp.70169","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T05:34:54Z","timestamp":1753680894000},"page":"3366-3377","source":"Crossref","is-referenced-by-count":8,"title":["Pharmacokinetics, pharmacodynamics and safety of casdatifan, a novel hypoxia\u2010inducible factor\u20102\u03b1 inhibitor, in healthy participants"],"prefix":"10.1002","volume":"91","author":[{"given":"Mohammad","family":"Ghasemi","sequence":"first","affiliation":[{"name":"Arcus Biosciences Hayward  California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji Yun","family":"Kim","sequence":"additional","affiliation":[{"name":"Arcus Biosciences Hayward  California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lisa","family":"Seitz","sequence":"additional","affiliation":[{"name":"Arcus Biosciences Hayward  California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixia","family":"Jin","sequence":"additional","affiliation":[{"name":"Arcus Biosciences Hayward  California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul G.","family":"Foster","sequence":"additional","affiliation":[{"name":"Arcus Biosciences Hayward  California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kai H.","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tzuling","family":"Cheng","sequence":"additional","affiliation":[{"name":"Arcus Biosciences Hayward  California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elaine","family":"Paterson","sequence":"additional","affiliation":[{"name":"Arcus Biosciences Hayward  California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Velinova","sequence":"additional","affiliation":[{"name":"ICON Early Clinical &amp; 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