{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T19:53:19Z","timestamp":1789501999534,"version":"build-2803163510"},"reference-count":29,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"},{"start":{"date-parts":[[2026,5,18]],"date-time":"2026-05-18T00:00:00Z","timestamp":1779062400000},"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":[[2026,9]]},"abstract":"<jats:p>\n                    Busulfan's narrow therapeutic index and high pharmacokinetic (PK) variability warrant investigation of its exposure\u2013toxicity relationship. We retrospectively analyzed 334 pediatric and young adult patients who underwent allogeneic hematopoietic stem cell transplantation at Seoul National University Children's Hospital between 2009 and 2020 and received once\u2010daily intravenous busulfan over four days (3\u2010hour infusion,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009122; 6\u2010hour infusion,\n                    <jats:italic>n<\/jats:italic>\n                    \u2009=\u2009212). Factors associated with toxicities were identified using multivariable logistic regression, and overall survival (OS) was evaluated by Kaplan\u2013Meier and Cox regression analyses. Despite comparable exposures, the 3\u2010hour infusion group showed higher\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    (4,260.2 vs 3,028.6\u2009\u03bcg\/L,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.0001) and more frequent liver function test elevations (13.1% vs 0.5%,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009&lt;\u20090.0001). Receiver operating characteristic analysis identified a\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    cut\u2010off of 4269.6\u2009\u03bcg\/L as a factor for hepatotoxicity. The 4\u2010year OS was superior in the 6\u2010hour infusion group (82.3% vs 71.9%,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.02) and in the low\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    group (80.8% vs 66.5%,\n                    <jats:italic>P<\/jats:italic>\n                    \u2009=\u20090.01). Cox regression revealed\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    as an independent predictor of OS. A population PK model was developed using NONMEM. A 1\u2010compartment model incorporating enzyme turnover auto\u2010inhibition successfully described the busulfan PK profile. Simulations of published once\u2010daily dosing regimens showed that extending the infusion to 6 hours successfully maintained\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    below the cut\u2010off threshold. These results show that maintaining busulfan\n                    <jats:italic>C<\/jats:italic>\n                    <jats:sub>max<\/jats:sub>\n                    below 4269.6\u2009\u03bcg\/L is associated with improved safety and survival. Prolonged infusion should be considered when adopting the busulfan once\u2010daily regimen.\n                  <\/jats:p>","DOI":"10.1002\/cpt.70337","type":"journal-article","created":{"date-parts":[[2026,5,19]],"date-time":"2026-05-19T03:26:32Z","timestamp":1779161192000},"page":"702-712","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Clinical Impact of Maximum Plasma Concentration of Busulfan in Pediatric Patients Undergoing Allogenic Hematopoietic Stem Cell Transplantation"],"prefix":"10.1002","volume":"120","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6584-9158","authenticated-orcid":false,"given":"Sungyeun","family":"Bae","sequence":"first","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics Seoul National University College of Medicine and Hospital  Seoul Korea"},{"name":"Department of Biomedical Sciences Seoul National University College of Medicine  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8758-3074","authenticated-orcid":false,"given":"Jung Yoon","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Seoul National University College of Medicine, Seoul National University Children's Hospital  Seoul Korea"},{"name":"Seoul National University Cancer Research Institute  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8822-1988","authenticated-orcid":false,"given":"Kyung Taek","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Seoul National University College of Medicine, Seoul National University Children's Hospital  Seoul Korea"},{"name":"Seoul National University Cancer Research Institute  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4671-0449","authenticated-orcid":false,"given":"Bo Kyung","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Seoul National University College of Medicine, Seoul National University Children's Hospital  Seoul Korea"},{"name":"Seoul National University Cancer Research Institute  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7062-0414","authenticated-orcid":false,"given":"Hyun Jin","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Seoul National University College of Medicine, Seoul National University Children's Hospital  Seoul Korea"},{"name":"Seoul National University Cancer Research Institute  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0921-7225","authenticated-orcid":false,"given":"Kyung\u2010Sang","family":"Yu","sequence":"additional","affiliation":[{"name":"Department of Clinical Pharmacology and Therapeutics Seoul National University College of Medicine and Hospital  Seoul Korea"},{"name":"Department of Biomedical Sciences Seoul National University College of Medicine  Seoul Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4010-0837","authenticated-orcid":false,"given":"Su\u2010jin","family":"Rhee","sequence":"additional","affiliation":[{"name":"Department of Pharmacy and Institute of Pharmaceutical Research, College of Pharmacy Wonkwang University  Iksan Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1009-6002","authenticated-orcid":false,"given":"Hyoung Jin","family":"Kang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Seoul National University College of Medicine, Seoul National University Children's Hospital  Seoul Korea"},{"name":"Seoul National University Cancer Research Institute  Seoul Korea"},{"name":"Wide River Institute of Immunology  Hongcheon Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2026,5,18]]},"reference":[{"key":"e_1_2_10_1_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-020-00947-2"},{"key":"e_1_2_10_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41409-024-02413-0"},{"key":"e_1_2_10_3_1","doi-asserted-by":"publisher","DOI":"10.1080\/17425255.2017.1360277"},{"key":"e_1_2_10_4_1","unstructured":"Highlights of prescribing information busulfex (Busulfan). FDA U(2015)."},{"key":"e_1_2_10_5_1","unstructured":"Product Information: busilvex; INN\u2010busulfan. EMA(2022)."},{"key":"e_1_2_10_6_1","doi-asserted-by":"publisher","DOI":"10.1007\/s40262-023-01275-x"},{"key":"e_1_2_10_7_1","doi-asserted-by":"publisher","DOI":"10.1016\/S2352-3026(16)30114-4"},{"key":"e_1_2_10_8_1","doi-asserted-by":"publisher","DOI":"10.1002\/hon.2789"},{"key":"e_1_2_10_9_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0012.2006.00581.x"},{"key":"e_1_2_10_10_1","doi-asserted-by":"publisher","DOI":"10.1038\/s41409-018-0281-7"},{"key":"e_1_2_10_11_1","doi-asserted-by":"publisher","DOI":"10.1186\/1756-8722-3-36"},{"key":"e_1_2_10_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtct.2022.10.024"},{"key":"e_1_2_10_13_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2011.11.025"},{"key":"e_1_2_10_14_1","doi-asserted-by":"publisher","DOI":"10.3345\/kjp.2016.59.11.S57"},{"key":"e_1_2_10_15_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.24734"},{"key":"e_1_2_10_16_1","doi-asserted-by":"publisher","DOI":"10.1097\/FTD.0b013e31829dc940"},{"key":"e_1_2_10_17_1","doi-asserted-by":"publisher","DOI":"10.1038\/bmt.2015.14"},{"key":"e_1_2_10_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2014.09.013"},{"key":"e_1_2_10_19_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2014.12.001"},{"key":"e_1_2_10_20_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbmt.2015.09.001"},{"key":"e_1_2_10_21_1","doi-asserted-by":"publisher","DOI":"10.1038\/bmt.2017.161"},{"key":"e_1_2_10_22_1","doi-asserted-by":"publisher","DOI":"10.1053\/bbmt.2002.v8.pm12374453"},{"key":"e_1_2_10_23_1","doi-asserted-by":"publisher","DOI":"10.1111\/bcp.14256"},{"key":"e_1_2_10_24_1","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-13-1960"},{"key":"e_1_2_10_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/psp4.12683"},{"key":"e_1_2_10_26_1","doi-asserted-by":"publisher","DOI":"10.2174\/138920008784746382"},{"key":"e_1_2_10_27_1","doi-asserted-by":"publisher","DOI":"10.1373\/jalm.2016.020412"},{"key":"e_1_2_10_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.molcel.2023.10.042"},{"key":"e_1_2_10_29_1","doi-asserted-by":"publisher","DOI":"10.1016\/0304-4165(89)90162-1"}],"container-title":["Clinical Pharmacology &amp; Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70337","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/cpt.70337","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/cpt.70337","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T20:36:00Z","timestamp":1785962160000},"score":1,"resource":{"primary":{"URL":"https:\/\/ascpt.onlinelibrary.wiley.com\/doi\/10.1002\/cpt.70337"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,18]]},"references-count":29,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2026,9]]}},"alternative-id":["10.1002\/cpt.70337"],"URL":"https:\/\/doi.org\/10.1002\/cpt.70337","archive":["Portico"],"relation":{},"ISSN":["0009-9236","1532-6535"],"issn-type":[{"value":"0009-9236","type":"print"},{"value":"1532-6535","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,18]]},"assertion":[{"value":"2025-12-29","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-04-30","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-05-18","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}