Precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: Results from a multicenter population pharmacokinetic study
Abstract Busulfan (Bu) is a common component of conditioning regimens before hematopoietic stem cell transplantation (HSCT) and is known for high interpatient pharmacokinetic (PK) variability. This study aimed to develop and externally validate a multicentric, population PK (PopPK) model for intrave...
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Online Access: | https://doi.org/10.1002/psp4.12683 |
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doaj-4a2a660863bf4f659cde9d7b20f139cd2021-09-20T19:32:58ZengWileyCPT: Pharmacometrics & Systems Pharmacology2163-83062021-09-011091043105610.1002/psp4.12683Precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: Results from a multicenter population pharmacokinetic studyKhalil Ben Hassine0Tiago Nava1Yves Théoret2Christa E. Nath3Youssef Daali4Nastya Kassir5Victor Lewis6Robbert G. M. Bredius7Peter J. Shaw8Henrique Bittencourt9Maja Krajinovic10Chakradhara Rao Satyanarayana Uppugunduri11Marc Ansari12CANSEARCH Research Platform in Pediatric Oncology and Hematology Department of Pediatrics, Gynecology and Obstetrics University of Geneva Geneva SwitzerlandCANSEARCH Research Platform in Pediatric Oncology and Hematology Department of Pediatrics, Gynecology and Obstetrics University of Geneva Geneva SwitzerlandCharles‐Bruneau Cancer Center Sainte‐Justine University Health Center (SJUHC) Montreal Quebec CanadaDepartment of Biochemistry The Children’s Hospital at Westmead Sydney New South Wales AustraliaClinical Pharmacology and Toxicology Division Geneva University Hospitals and University of Geneva Geneva SwitzerlandGenentech/RocheClinical Pharmacology South San Francisco California USADepartment of Pediatrics Alberta Children's Hospital Calgary Alberta CanadaDepartment of Pediatrics Leiden University Medical Center Leiden The NetherlandsThe Cancer Centre for Children The Children’s Hospital at Westmead Sydney New South Wales AustraliaCharles‐Bruneau Cancer Center Sainte‐Justine University Health Center (SJUHC) Montreal Quebec CanadaCharles‐Bruneau Cancer Center Sainte‐Justine University Health Center (SJUHC) Montreal Quebec CanadaCANSEARCH Research Platform in Pediatric Oncology and Hematology Department of Pediatrics, Gynecology and Obstetrics University of Geneva Geneva SwitzerlandCANSEARCH Research Platform in Pediatric Oncology and Hematology Department of Pediatrics, Gynecology and Obstetrics University of Geneva Geneva SwitzerlandAbstract Busulfan (Bu) is a common component of conditioning regimens before hematopoietic stem cell transplantation (HSCT) and is known for high interpatient pharmacokinetic (PK) variability. 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‐s‐transferase A1 (GSTA1) polymorphisms on Bu's PK in a large multicentric pediatric population while accounting for fludarabine (Flu) coadministration and, second, to establish an individualized, model‐based, first‐dose 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‐based 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‐dependent allometric scaling of a body weight model. A stepwise covariate analysis identified Day 1 of Bu conditioning, GSTA1 metabolic groups based on GSTA1 polymorphisms, and Flu coadministration as significant covariates influencing Bu CL. The final model adequately predicted Bu first‐dose 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, −0.5%; 95% confidence interval [CI], −3.1% to 2.0%) and acceptable precision (mean absolute prediction error percentage, 18.7%; 95% CI, 17.0%–20.5%) in Bu CL prediction for dosing. This multicentric PopPK study confirmed the influence of GSTA1 polymorphisms and Flu coadministration on Bu CL. The developed model accurately predicted Bu CL and first doses in an external cohort of pediatric patients.https://doi.org/10.1002/psp4.12683 |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Khalil Ben Hassine Tiago Nava Yves Théoret Christa E. Nath Youssef Daali Nastya Kassir Victor Lewis Robbert G. M. Bredius Peter J. Shaw Henrique Bittencourt Maja Krajinovic Chakradhara Rao Satyanarayana Uppugunduri Marc Ansari |
spellingShingle |
Khalil Ben Hassine Tiago Nava Yves Théoret Christa E. Nath Youssef Daali Nastya Kassir Victor Lewis Robbert G. M. Bredius Peter J. Shaw Henrique Bittencourt Maja Krajinovic Chakradhara Rao Satyanarayana Uppugunduri Marc Ansari Precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: Results from a multicenter population pharmacokinetic study CPT: Pharmacometrics & Systems Pharmacology |
author_facet |
Khalil Ben Hassine Tiago Nava Yves Théoret Christa E. Nath Youssef Daali Nastya Kassir Victor Lewis Robbert G. M. Bredius Peter J. Shaw Henrique Bittencourt Maja Krajinovic Chakradhara Rao Satyanarayana Uppugunduri Marc Ansari |
author_sort |
Khalil Ben Hassine |
title |
Precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: Results from a multicenter population pharmacokinetic study |
title_short |
Precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: Results from a multicenter population pharmacokinetic study |
title_full |
Precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: Results from a multicenter population pharmacokinetic study |
title_fullStr |
Precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: Results from a multicenter population pharmacokinetic study |
title_full_unstemmed |
Precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: Results from a multicenter population pharmacokinetic study |
title_sort |
precision dosing of intravenous busulfan in pediatric hematopoietic stem cell transplantation: results from a multicenter population pharmacokinetic study |
publisher |
Wiley |
series |
CPT: Pharmacometrics & Systems Pharmacology |
issn |
2163-8306 |
publishDate |
2021-09-01 |
description |
Abstract Busulfan (Bu) is a common component of conditioning regimens before hematopoietic stem cell transplantation (HSCT) and is known for high interpatient pharmacokinetic (PK) variability. 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‐s‐transferase A1 (GSTA1) polymorphisms on Bu's PK in a large multicentric pediatric population while accounting for fludarabine (Flu) coadministration and, second, to establish an individualized, model‐based, first‐dose 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‐based 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‐dependent allometric scaling of a body weight model. A stepwise covariate analysis identified Day 1 of Bu conditioning, GSTA1 metabolic groups based on GSTA1 polymorphisms, and Flu coadministration as significant covariates influencing Bu CL. The final model adequately predicted Bu first‐dose 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, −0.5%; 95% confidence interval [CI], −3.1% to 2.0%) and acceptable precision (mean absolute prediction error percentage, 18.7%; 95% CI, 17.0%–20.5%) in Bu CL prediction for dosing. This multicentric PopPK study confirmed the influence of GSTA1 polymorphisms and Flu coadministration on Bu CL. The developed model accurately predicted Bu CL and first doses in an external cohort of pediatric patients. |
url |
https://doi.org/10.1002/psp4.12683 |
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