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This study aimed to develop and externally validate a multicentric, population PK (PopPK) model for intravenous Bu in pediatric patients before HSCT to first study the influence of glutathione\u2010s\u2010transferase A1 (<jats:italic>GSTA1<\/jats:italic>) polymorphisms on Bu's PK in a large multicentric pediatric population while accounting for fludarabine (Flu) coadministration and, second, to establish an individualized, model\u2010based, first\u2010dose recommendation for intravenous Bu that can be widely used in pediatric patients. The model was built using data from 302 patients from five transplantation centers who received a Bu\u2010based conditioning regimen. External model validation used data from 100 patients. The relationship between body weight and Bu clearance (CL) was best described by an age\u2010dependent allometric scaling of a body weight model. A stepwise covariate analysis identified Day 1 of Bu conditioning, GSTA1\u00a0metabolic groups based on <jats:italic>GSTA1<\/jats:italic> polymorphisms, and Flu coadministration as significant covariates influencing Bu CL. The final model adequately predicted Bu first\u2010dose CL in the external cohort, with 81% of predicted area under the curves within the therapeutic window. The final model showed minimal bias (mean prediction error, \u22120.5%; 95% confidence interval [CI], \u22123.1% to 2.0%) and acceptable precision (mean absolute prediction error percentage,\u00a018.7%; 95% CI, 17.0%\u201320.5%) in Bu CL prediction for dosing. This multicentric PopPK study confirmed the influence of <jats:italic>GSTA1<\/jats:italic> polymorphisms and Flu coadministration on Bu CL. The developed model accurately predicted Bu CL and first doses in an external cohort of pediatric patients.<\/jats:p>","DOI":"10.1002\/psp4.12683","type":"journal-article","created":{"date-parts":[[2021,8,28]],"date-time":"2021-08-28T09:45:48Z","timestamp":1630143948000},"page":"1043-1056","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":28,"title":["Precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: Results from a multicenter population pharmacokinetic study"],"prefix":"10.1002","volume":"10","author":[{"given":"Khalil","family":"Ben Hassine","sequence":"first","affiliation":[{"name":"CANSEARCH Research Platform in Pediatric Oncology and Hematology Department of Pediatrics, Gynecology and Obstetrics University of Geneva Geneva Switzerland"},{"name":"Division of Pediatric Oncology and Hematology Department of Pediatrics, Gynecology and Obstetrics Geneva University Hospitals and University of Geneva Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tiago","family":"Nava","sequence":"additional","affiliation":[{"name":"CANSEARCH Research Platform in Pediatric Oncology and Hematology Department of Pediatrics, Gynecology and Obstetrics University of Geneva Geneva Switzerland"},{"name":"Division of Pediatric Oncology and Hematology Department of Pediatrics, Gynecology and Obstetrics Geneva University Hospitals and University of Geneva Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yves","family":"Th\u00e9oret","sequence":"additional","affiliation":[{"name":"Charles\u2010Bruneau Cancer Center Sainte\u2010Justine University Health Center (SJUHC) Montreal Quebec Canada"},{"name":"Department of Pharmacology and Physiology Faculty of Medicine University of Montreal Montreal Quebec Canada"},{"name":"Clinical Pharmacology Unit Sainte\u2010Justine University Health Center (SJUHC) Montreal Quebec Canada"},{"name":"Department of Pediatrics Faculty of Medicine University of Montreal Montreal Quebec Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christa E.","family":"Nath","sequence":"additional","affiliation":[{"name":"Department of Biochemistry The Children\u2019s Hospital at Westmead Sydney New South Wales Australia"},{"name":"The Cancer Centre for Children The Children\u2019s Hospital at Westmead Sydney New South Wales Australia"},{"name":"Children's Hospital at Westmead Clinical School Faculty of Medicine and Health The University of Sydney Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youssef","family":"Daali","sequence":"additional","affiliation":[{"name":"Clinical Pharmacology and Toxicology Division Geneva University Hospitals and University of Geneva Geneva Switzerland"},{"name":"Faculty of Medicine &amp; Sciences University of Geneva Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nastya","family":"Kassir","sequence":"additional","affiliation":[{"name":"Genentech\/Roche Clinical Pharmacology South San Francisco California USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Alberta Children's Hospital Calgary Alberta Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robbert G. M.","family":"Bredius","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Leiden University Medical Center Leiden The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Shaw","sequence":"additional","affiliation":[{"name":"The Cancer Centre for Children The Children\u2019s Hospital at Westmead Sydney New South Wales Australia"},{"name":"Children's Hospital at Westmead Clinical School Faculty of Medicine and Health The University of Sydney Sydney New South Wales Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henrique","family":"Bittencourt","sequence":"additional","affiliation":[{"name":"Charles\u2010Bruneau Cancer Center Sainte\u2010Justine University Health Center (SJUHC) Montreal Quebec Canada"},{"name":"Department of Pharmacology and Physiology Faculty of Medicine University of Montreal Montreal Quebec Canada"},{"name":"Clinical Pharmacology Unit Sainte\u2010Justine University Health 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Obstetrics University of Geneva Geneva Switzerland"},{"name":"Division of Pediatric Oncology and Hematology Department of Pediatrics, Gynecology and Obstetrics Geneva University Hospitals and University of Geneva Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marc","family":"Ansari","sequence":"additional","affiliation":[{"name":"CANSEARCH Research Platform in Pediatric Oncology and Hematology Department of Pediatrics, Gynecology and Obstetrics University of Geneva Geneva Switzerland"},{"name":"Division of Pediatric Oncology and Hematology Department of Pediatrics, Gynecology and Obstetrics Geneva University Hospitals and University of Geneva Geneva Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,8,28]]},"reference":[{"key":"e_1_2_11_2_1","first-page":"31","article-title":"Graft\u2010rejection and toxicity following bone marrow transplantation in relation to busulfan 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