{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T17:15:26Z","timestamp":1787505326983,"version":"build-2736575974"},"reference-count":64,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T00:00:00Z","timestamp":1762732800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"IL-YANG Pharmaceutical Co., Ltd."},{"name":"Research Institute of Pharmaceutical Sciences of Seoul National University"},{"name":"Research Institute of Pharmaceutical Sciences of Seoul National University"},{"DOI":"10.13039\/501100003569","name":"Ministry of Food and Drug Safety of Korea","doi-asserted-by":"crossref","award":["21153MFDS601-1"],"award-info":[{"award-number":["21153MFDS601-1"]}],"id":[{"id":"10.13039\/501100003569","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100003569","name":"Ministry of Food and Drug Safety of Korea","doi-asserted-by":"crossref","award":["RS-2024-00331810"],"award-info":[{"award-number":["RS-2024-00331810"]}],"id":[{"id":"10.13039\/501100003569","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Radotinib is a second-generation tyrosine kinase inhibitor (TKI) that has been used for treatment of chronic myeloid leukemia (CML). This study was performed for the first time to characterize the pharmacokinetics of radotinib, identify the factors contributing to pharmacokinetic variabilities and explore alternative dosing regimens. Methods: A total of 640 plasma concentration\u2013time datapoints obtained from 47 participants were evaluated using nonlinear mixed-effects modeling to estimate pharmacokinetic parameters and evaluate covariate effects. The study population comprised 23 healthy volunteers (HVs) who received a single, oral dose of 400 mg radotinib and 24 CML patients who repeatedly received 300 mg twice daily. Based on the final population pharmacokinetic model, alternative dosing regimens to the current every 12 h regimen were explored using Monte Carlo simulations. Results: A two-compartment model with first-order absorption through transit compartments and first-order elimination incorporating a circadian rhythm effect best described radotinib pharmacokinetics. Disease status significantly affected apparent clearance; it was slower by 39.2% in CML patients compared with HVs (23.0 L\/h versus 37.9 L\/h), resulting in a longer terminal half-life (28.8 h versus 17.5 h). Age was negatively associated with volume of distribution in the central compartment, with an estimated slope of \u22120.0129 L\/year. A 400 mg once-daily regimen was predicted to provide comparable systemic exposures to those of other TKIs with similar physiochemical and pharmacological properties to radotinib, and a 36% lower exposure than that of the current 300 mg twice-daily regimen. Conclusions: The model developed in this study adequately describes the population pharmacokinetics of radotinib and provides a basis for optimal, individualized radotinib therapy for patients with CML.<\/jats:p>","DOI":"10.3390\/ph18111705","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T13:51:08Z","timestamp":1762782668000},"page":"1705","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Population Pharmacokinetics of Radotinib in Healthy Volunteers and Patients with Chronic Myeloid Leukemia"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0006-6818-5226","authenticated-orcid":false,"given":"Minseo","family":"Kang","sequence":"first","affiliation":[{"name":"College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiwon","family":"Kim","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yerin","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-7227-9551","authenticated-orcid":false,"given":"Jae Soo","family":"Shin","sequence":"additional","affiliation":[{"name":"IL-YANG Pharmaceutical Co., Ltd., Yongin 17096, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4395-9938","authenticated-orcid":false,"given":"Min Soo","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7131-0522","authenticated-orcid":false,"given":"Qian","family":"Jiang","sequence":"additional","affiliation":[{"name":"Peking University People\u2019s Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing 100044, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9200-2799","authenticated-orcid":false,"given":"Eun Kyoung","family":"Chung","sequence":"additional","affiliation":[{"name":"Departments of Pharmacy and Regulatory Science, College of Pharmacy, Kyung Hee University, Seoul 02447, Republic of Korea"},{"name":"Institutes of Regulatory Innovation Through Science (IRIS) and Integrated Pharmaceutical Sciences, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5565-8323","authenticated-orcid":false,"given":"Jangik I.","family":"Lee","sequence":"additional","affiliation":[{"name":"College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/243290a0","article-title":"Letter: A new consistent chromosomal abnormality in chronic myelogenous leukaemia identified by quinacrine fluorescence and Giemsa staining","volume":"243","author":"Rowley","year":"1973","journal-title":"Nature"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"261","DOI":"10.2147\/JBM.S382090","article-title":"Chronic Myeloid Leukemia, from Pathophysiology to Treatment-Free Remission: A Narrative Literature Review","volume":"14","author":"Rinaldi","year":"2023","journal-title":"J. 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