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Daily serial blood sampling was performed and concentration\u2010time data were analyzed using a nonlinear mixed\u2010effects approach. The developed PK model was used to assess achievement of target exposure under six dose\u2010adjustment scenarios based on simulations performed in RStudio (RxODE package)\u00ae. A total of 2491 busulfan plasma concentration\u2013time measurements were collected from 95 patients characterizing 379 dosing days. A two\u2010compartment model with time\u2010associated CL best described the data with a typical CL of 14.5\u00a0L\/h for an adult male with 62\u2009kg normal fat mass (NFM; equivalent to 70\u2009kg total body weight), typical volume of distribution central compartment (V1) of 40.6\u00a0L\/59\u2009kg NFM (equivalent to 70\u2009kg total body weight), and typical volume of distribution peripheral compartment of 3.57\u2009L\/62\u2009kg NFM. Model interindividual variability in CL and V1 was 14.7% and 34.9%, respectively, and interoccasional variability in CL was 6.6%. Patient size described by NFM, a maturation component, and time since start of treatment significantly influenced CL. Simulations demonstrated that using model\u2010based exposure estimates with each dose, and either a proportional dose\u2010adjustment calculation or model\u2010based calculated individual CL estimates to support dose adjustments, increased proportion of subjects attaining cumulative exposure within 5% of target compared with using noncompartmental analysis (100% vs. 0%). A time\u2010associated reduction in CL during once\u2010daily busulfan treatment was described.<\/jats:p>","DOI":"10.1002\/psp4.12809","type":"journal-article","created":{"date-parts":[[2022,5,25]],"date-time":"2022-05-25T12:14:56Z","timestamp":1653480896000},"page":"1002-1017","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Population pharmacokinetic model for once\u2010daily intravenous busulfan in pediatric subjects describing <scp>time\u2010associated<\/scp> clearance"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0104-5396","authenticated-orcid":false,"given":"Rachael","family":"Lawson","sequence":"first","affiliation":[{"name":"School of Pharmacy University of Queensland  Brisbane Queensland Australia"},{"name":"Pharmacy Department Queensland Children's Hospital  Brisbane Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine E.","family":"Staatz","sequence":"additional","affiliation":[{"name":"School of Pharmacy University of Queensland  Brisbane Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher J.","family":"Fraser","sequence":"additional","affiliation":[{"name":"Blood and Marrow Transplant Service Queensland Children's Hospital  Brisbane Queensland Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shanti","family":"Ramachandran","sequence":"additional","affiliation":[{"name":"Oncology Department Perth Children's Hospital  Perth Western Australia Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lochie","family":"Teague","sequence":"additional","affiliation":[{"name":"Pediatric Blood and Cancer Centre Starship Hospital  Auckland New Zealand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Kids Cancer Centre Sydney Children's Hospital  Randwick New South Wales Australia"},{"name":"School of Women &amp; Children's Health University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tracey","family":"O'Brien","sequence":"additional","affiliation":[{"name":"Kids Cancer Centre Sydney Children's Hospital  Randwick New South Wales Australia"},{"name":"School of Women &amp; Children's Health University of New South Wales  Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5972-3711","authenticated-orcid":false,"given":"Stefanie","family":"Hennig","sequence":"additional","affiliation":[{"name":"Certara, Inc.  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