TY - JOUR
T1 - Evaluation of the pharmacokinetics of prednisolone in paediatric patients with acute lymphoblastic leukaemia treated according to Dutch Childhood Oncology Group protocols and its relation to treatment response
AU - Sassen, Sebastiaan D. T.
AU - Mathôt, Ron A. A.
AU - Pieters, Rob
AU - de Haas, Valérie
AU - Kaspers, Gertjan J. L.
AU - van den Bos, Cor
AU - Tissing, Wim J. E.
AU - te Loo, D. Maroeska W. W.
AU - Bierings, Marc B.
AU - van der Sluis, Inge M.
AU - Zwaan, C. Michel
N1 - Funding Information: This study was funded by the Children Cancer-free (KiKa) Foundation and the Go4Children Foundation. We thank all patients for collaboration in this study. We thank the patients and their parents, participating centres and (research) nurses for their help. We thank Marcel Pistorius of the Department of Hospital Pharmacy of the Amsterdam University Academic Centers in Amsterdam, the Netherlands for the analysis of the samples. This study was funded by the Children Cancer-free (KiKa) Foundation and the Go4Children Foundation. Ron Math?t, Michel Zwaan and Sebastiaan Sassen designed the study, performed the study and analysed the data; Sebastiaan Sassen wrote the paper; Michel Zwaan and Ron Math?t critically revised the paper; Michel Zwaan, Rob Pieters, Val?rie de Haas, Gertjan Kaspers, Cor van den Bos, Wim Tissing, Maroeska te Loo, Marc Bierings and Inge van der Sluis made substantial contributions to the acquisition of data and critical revision of the drafted article. Funding Information: We thank the patients and their parents, participating centres and (research) nurses for their help. We thank Marcel Pistorius of the Department of Hospital Pharmacy of the Amsterdam University Academic Centers in Amsterdam, the Netherlands for the analysis of the samples. This study was funded by the Children Cancer‐free (KiKa) Foundation and the Go4Children Foundation. Ron Mathôt, Michel Zwaan and Sebastiaan Sassen designed the study, performed the study and analysed the data; Sebastiaan Sassen wrote the paper; Michel Zwaan and Ron Mathôt critically revised the paper; Michel Zwaan, Rob Pieters, Valérie de Haas, Gertjan Kaspers, Cor van den Bos, Wim Tissing, Maroeska te Loo, Marc Bierings and Inge van der Sluis made substantial contributions to the acquisition of data and critical revision of the drafted article. Publisher Copyright: © 2021 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd. Copyright: Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/7/1
Y1 - 2021/7/1
N2 - Glucocorticoids form the backbone of paediatric acute lymphoblastic leukaemia (ALL) treatment. Many studies have been performed on steroid resistance; however, few studies have addressed the relationship between dose, concentration and clinical response. The aim of the present study was to evaluate the pharmacokinetics of prednisolone in the treatment of paediatric ALL and the correlation with clinical parameters. A total of 1028 bound and unbound prednisolone plasma concentrations were available from 124 children (aged 0–18 years) with newly diagnosed ALL enrolled in the Dutch Childhood Oncology Group studies. A population pharmacokinetic model was developed and post hoc area under the curve (AUC) was tested against treatment outcome parameters. The pharmacokinetics of unbound prednisolone in plasma was best described with allometric scaling and saturable binding to proteins. Plasma protein binding decreased with age. The AUC of unbound prednisolone was not associated with any of the disease parameters or treatment outcomes. Unbound prednisolone plasma concentrations correlated with age. No effect of exposure on clinical treatment outcome parameters was observed and does not substantiate individualised dosing. Poor responders, high-risk and relapsed patients showed a trend towards lower exposure compared to good responders. However, the group of poor responders was small and requires further research.
AB - Glucocorticoids form the backbone of paediatric acute lymphoblastic leukaemia (ALL) treatment. Many studies have been performed on steroid resistance; however, few studies have addressed the relationship between dose, concentration and clinical response. The aim of the present study was to evaluate the pharmacokinetics of prednisolone in the treatment of paediatric ALL and the correlation with clinical parameters. A total of 1028 bound and unbound prednisolone plasma concentrations were available from 124 children (aged 0–18 years) with newly diagnosed ALL enrolled in the Dutch Childhood Oncology Group studies. A population pharmacokinetic model was developed and post hoc area under the curve (AUC) was tested against treatment outcome parameters. The pharmacokinetics of unbound prednisolone in plasma was best described with allometric scaling and saturable binding to proteins. Plasma protein binding decreased with age. The AUC of unbound prednisolone was not associated with any of the disease parameters or treatment outcomes. Unbound prednisolone plasma concentrations correlated with age. No effect of exposure on clinical treatment outcome parameters was observed and does not substantiate individualised dosing. Poor responders, high-risk and relapsed patients showed a trend towards lower exposure compared to good responders. However, the group of poor responders was small and requires further research.
KW - NONMEM
KW - acute lymphoblastic leukaemia
KW - dexamethasone
KW - paediatrics
KW - pharmacokinetics/pharmacodynamics
KW - prednisolone
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85107287211&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/34060065
UR - http://www.scopus.com/inward/record.url?scp=85107287211&partnerID=8YFLogxK
U2 - https://doi.org/10.1111/bjh.17572
DO - https://doi.org/10.1111/bjh.17572
M3 - Article
C2 - 34060065
SN - 0007-1048
VL - 194
SP - 423
EP - 432
JO - British journal of haematology
JF - British journal of haematology
IS - 2
ER -