{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T09:34:46Z","timestamp":1787045686003,"version":"build-2736575974"},"reference-count":31,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["R01CA255124"],"award-info":[{"award-number":["R01CA255124"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P30CA022453"],"award-info":[{"award-number":["P30CA022453"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"award":["R01CA255124"],"award-info":[{"award-number":["R01CA255124"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]},{"award":["P30CA022453"],"award-info":[{"award-number":["P30CA022453"]}],"id":[{"id":"https:\/\/ror.org\/040gcmg81","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: This study aimed to evaluate the potential utility of plasma 4\u03b2-hydroxycholesterol (4\u03b2-OHC) as an endogenous biomarker of hepatic CYP3A activity for predicting ribociclib metabolism and systemic pharmacokinetics in patients with primary brain cancer. Methods: Plasma concentration data for ribociclib and its major metabolite, LEQ803, were obtained from 46 patients receiving oral ribociclib at daily doses of 400, 600, or 900 mg for 5 days. Plasma 4\u03b2-OHC concentrations and 4\u03b2-OHC\/cholesterol ratios were determined by LC\u2013MS\/MS at baseline and at 4 and 24 h after ribociclib administration on day 5. A parent\u2013metabolite population pharmacokinetic model was developed to simultaneously characterize ribociclib and LEQ803 disposition and identify clinical covariates influencing their pharmacokinetics.\u00a0Results: The parent\u2013metabolite model adequately described the multiple-dose plasma concentration\u2013time profiles of ribociclib and LEQ803. On-treatment plasma 4\u03b2-OHC concentration was identified as a significant predictor for CYP3A-mediated ribociclib metabolism to LEQ803, accounting for ~36% of interindividual variability in the metabolic clearance. Plasma 4\u03b2-OHC showed limited ability to predict total apparent oral clearance or systemic exposure of ribociclib. Conclusions: These findings support the clinical utility of plasma 4\u03b2-OHC as an endogenous biomarker of hepatic CYP3A activity for predicting CYP3A-mediated metabolism of substrate drugs such as ribociclib, while highlighting its limitation for predicting total apparent oral clearance of drugs undergoing intestinal first-pass metabolism and elimination through multiple pathways. These results underscore the importance of considering the relative contribution of hepatic CYP3A metabolism to overall drug disposition when evaluating translational utility of endogenous CYP3A biomarkers in clinical pharmacology.<\/jats:p>","DOI":"10.3390\/cancers18162667","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T09:06:41Z","timestamp":1787044001000},"page":"2667","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Plasma 4\u03b2-Hydroxycholesterol Predicts Ribociclib CYP3A-Mediated Metabolism, but Not Plasma Exposure, in Patients with Primary Brain Cancer"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8002-0632","authenticated-orcid":false,"given":"Charuka","family":"Wickramasinghe","sequence":"first","affiliation":[{"name":"Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R Street, HWCRC, Room 523, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xun","family":"Bao","sequence":"additional","affiliation":[{"name":"Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R Street, HWCRC, Room 523, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanyuan","family":"Jiang","sequence":"additional","affiliation":[{"name":"Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R Street, HWCRC, Room 523, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9590-9951","authenticated-orcid":false,"given":"Jun","family":"Jiang","sequence":"additional","affiliation":[{"name":"Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R Street, HWCRC, Room 523, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Yue","sequence":"additional","affiliation":[{"name":"Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R Street, HWCRC, Room 523, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nader","family":"Sanai","sequence":"additional","affiliation":[{"name":"Barrow Neurological Institute, St. Joseph\u2019s Hospital & Medical Center, Phoenix, AZ 85004, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9924-1386","authenticated-orcid":false,"given":"Jing","family":"Li","sequence":"additional","affiliation":[{"name":"Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R Street, HWCRC, Room 523, Detroit, MI 48201, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1093\/neuonc\/noaf257","article-title":"Single-nucleus transcriptomics, pharmacokinetics, and pharmacodynamics of CDK4\/6 and mTOR inhibition in a Phase 0\/1 trial of recurrent high-grade glioma","volume":"28","author":"Johnson","year":"2026","journal-title":"Neuro-Oncol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ccell.2018.03.023","article-title":"CDK4\/6 Inhibitors: The Mechanism of Action May Not Be as Simple as Once Thought","volume":"34","author":"Klein","year":"2018","journal-title":"Cancer Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1002\/cpt.2021","article-title":"Physiologically Based Pharmacokinetic Modeling of Central Nervous System Pharmacokinetics of CDK4\/6 Inhibitors to Guide Selection of Drug and Dosing Regimen for Brain Cancer Treatment","volume":"109","author":"Li","year":"2021","journal-title":"Clin. 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