Towards optimization of dexamethasone therapy in the maintenance phase of pediatric acute lymphoblastic leukemia: A population pharmacokinetic and pharmacodynamic study of dexamethasone and metabolite

Dexamethasone is crucial in pediatric acute lymphoblastic leukemia (ALL) treatment, however, studies regarding the pharmacokinetics of dexamethasone and its metabolites are scarce. Our study conducted a comprehensive pharmacokinetic-pharmacodynamic analysis of dexamethasone and metabolite, examining...

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Bibliographic Details
Published in:	European journal of pharmaceutical sciences Vol. 204; p. 106964
Main Authors:	Li, Letao, van Hulst, Annelienke M., Verwaaijen, Emma J., van den Heuvel-Eibrink, M.(Marry), van den Akker, E.L.T.(Erica), Rietdijk, W (Wim) J R, Koch, B.C.P.(Birgit), Sassen, S.D.T.(Sebastiaan)
Format:	Journal Article
Language:	English
Published:	Elsevier B.V 01-01-2025
Subjects:	Acute lymphoblastic leukemia CYP3A4 Dexamethasone Drug-drug interaction Pharmacokinetic-pharmacodynamic study Dexamethasone Pharmacokinetic-pharmacodynamic study Acute lymphoblastic leukemia CYP3A4 Drug-drug interaction
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Summary:	Dexamethasone is crucial in pediatric acute lymphoblastic leukemia (ALL) treatment, however, studies regarding the pharmacokinetics of dexamethasone and its metabolites are scarce. Our study conducted a comprehensive pharmacokinetic-pharmacodynamic analysis of dexamethasone and metabolite, examining their association with dexamethasone-induced toxicity. Peak and trough concentrations were collected during the maintenance phase from pediatric ALL patients who received oral dexamethasone (6mg/m2/day). NONMEM was used to study the population pharmacokinetics including covariates. Pharmacokinetic (PK) and pharmacodynamic (PD) correlations between drug and its active metabolite exposure and adverse effects were examined. 382 samples (dexamethasone: n = 191; 6β-hydroxydexamethasone: n = 191) from 104 children (age range 3.0 -18.8 years) were collected. A one-compartment model described the data best. The estimated apparent dexamethasone total clearance was 26 L/h/70 kg with 18 % inter-individual variability, and an apparent volume of distribution of 123 L/70 kg, yielding a half-life of 3.3 h. Covariate analysis demonstrated that when asparaginase was co-administered, there was a 50 % reduction in both the clearance of dexamethasone and the extent to which dexamethasone was metabolized to 6β-hydroxydexamethasone. A statistically significant but weak positive correlation was observed between dexamethasone drug exposure and fasting hunger scores. Dexamethasone exposure significantly increased with asparaginase co-administration by inhibition of the CYP3A4 pathway. Our study found a statistically significant but weak positive correlation between dexamethasone exposure and increased hunger. These results support the need for more studies on how to personalize dexamethasone dosing in pediatric ALL treatment and adjust doses to limit side effects, especially in case of co-medication. [Display omitted]
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0928-0987 1879-0720 1879-0720
DOI:	10.1016/j.ejps.2024.106964