{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:20:06Z","timestamp":1790612406215,"version":"4.1.0"},"reference-count":31,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"},{"start":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T00:00:00Z","timestamp":1768521600000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["ascpt.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Clin Pharma and Therapeutics"],"published-print":{"date-parts":[[2026,4]]},"abstract":"<jats:p>\n                    Fezolinetant is a first\u2010in\u2010class, selective, non\u2010hormonal, neurokinin 3 receptor antagonist that is approved for the treatment of moderate to severe vasomotor symptoms due to menopause. In a phase 2b clinical study (\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009352), nine study participants experienced elevations in serum transaminases exceeding three times the upper limit of normal. DILIsym, a quantitative systems toxicology model of drug\u2010induced liver injury, was used to assess the potential hepatotoxicity of fezolinetant prior to initiating phase 3 trials.\n                    <jats:italic>In vitro<\/jats:italic>\n                    toxicity assays and physiologically\u2010based pharmacokinetic estimates of fezolinetant and primary metabolite exposure were leveraged to simulate the incidence of hepatotoxicity for various fezolinetant treatment regimens and virtual simulated populations. DILIsym simulations indicated a dose\u2010dependent relationship between fezolinetant exposure and hepatotoxicity primarily caused by electron transport chain inhibition. At therapeutic doses, no ALT elevations exceeding three times the upper limit of normal were predicted for healthy volunteers. In a metabolic syndrome\u2010associated fatty liver disease (MAFLD) population with compromised mitochondrial function, mild increases in ALT elevation frequency above placebo were observed in all fezolinetant treatment groups and included a single Hy\u2019s Law case at 45 and 60\u2009mg once daily. The predicted Hy\u2019s Law case in the MAFLD population was mitigated by the incorporation of mitochondrial biogenesis. These predictions aided discussions with internal and external stakeholders regarding dose selection and initiation of the phase 3 clinical studies. Phase 3 studies were subsequently completed and confirmed the efficacy and acceptable liver safety of fezolinetant at 30 and 45\u2009mg QD, leading to drug approval at 45\u2009mg QD.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70194","type":"journal-article","created":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T08:06:19Z","timestamp":1768550779000},"page":"1016-1024","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Quantitative Systems Toxicology Modeling with DILIsym to Support Phase 3 Dose Selection for Fezolinetant"],"prefix":"10.1002","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-4950-7957","authenticated-orcid":false,"given":"Jace C.","family":"Nielsen","sequence":"first","affiliation":[{"name":"Astellas Pharma Global Development, Inc.  Northbrook Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-3326-1210","authenticated-orcid":false,"given":"Jeffrey L.","family":"Woodhead","sequence":"additional","affiliation":[{"name":"Simulations Plus, Inc.  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2815-2084","authenticated-orcid":false,"given":"Brett A.","family":"Howell","sequence":"additional","affiliation":[{"name":"Simulations Plus, Inc.  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9310-0080","authenticated-orcid":false,"given":"Lisl K. M.","family":"Shoda","sequence":"additional","affiliation":[{"name":"Simulations Plus, Inc.  Research Triangle Park North Carolina USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3072-1784","authenticated-orcid":false,"given":"Dolly A.","family":"Parasrampuria","sequence":"additional","affiliation":[{"name":"Astellas Pharma Global Development, Inc.  Northbrook Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiayin","family":"Huang","sequence":"additional","affiliation":[{"name":"Astellas Pharma Global Development, Inc.  Northbrook Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-4323-8266","authenticated-orcid":false,"given":"Megumi","family":"Iwai","sequence":"additional","affiliation":[{"name":"Astellas Pharma Global Development, Inc.  Northbrook Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6295-5166","authenticated-orcid":false,"given":"Faith D.","family":"Ottery","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3771-0762","authenticated-orcid":false,"given":"Xuegong","family":"Wang","sequence":"additional","affiliation":[{"name":"Astellas Pharma Global Development, Inc.  Northbrook Illinois USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3600-5677","authenticated-orcid":false,"given":"Marci","family":"English","sequence":"additional","affiliation":[{"name":"Astellas Pharma Global Development, Inc.  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Accessed April 24 2025."},{"key":"e_1_2_9_2_1","unstructured":"PrVEOZAH\u00ae; fezolinetant tablets; tablet 45 mg oral; other gynecologicals (G02CX06)Product monograph: including patient medication information. <https:\/\/pdf.hres.ca\/dpd_pm\/00077931.PDF> (2024). Accessed April 24 2025."},{"key":"e_1_2_9_3_1","unstructured":"Veoza 45 mg film\u2010coated tablets Annex I: summary of product characteristics<https:\/\/www.ema.europa.eu\/en\/documents\/product\u2010information\/veoza\u2010epar\u2010product\u2010information_en.pdf> (2023). Accessed April 24 2025."},{"key":"e_1_2_9_4_1","unstructured":"Veoza 45 mg film\u2010coated tablets summary of product characteristics<https:\/\/mhraproducts4853.blob.core.windows.net\/docs\/e6b1f8b85b2a5341888c20a91f33d0d51894054b> (2025). Accessed April 24 2025."},{"key":"e_1_2_9_5_1","unstructured":"Veoza\u2122.Date of revision of the texthttps:\/\/ndi.fda.moph.go.th\/uploads\/drug_detail_corporation\/doc\/word\/1263\/7c4b97727e0e458e6b8908689db94332\u2010a1.pdf(2025). Accessed April 24 2025."},{"key":"e_1_2_9_6_1","unstructured":"Australian product information \u2010 VEOZA\u2122 (Fezolinetant)<https:\/\/www.ebs.tga.gov.au\/ebs\/picmi\/picmirepository.nsf\/pdf?OpenAgent=&id=CP\u20102024\u2010PI\u201001388\u20101&d=20240314172310101> (2024). 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