Overestimation of the effect of (fos)aprepitant on intravenous dexamethasone pharmacokinetics requires adaptation of the guidelines for children with chemotherapy-induced nausea and vomiting

A. Laura Nijstad, Evelien de Vos-Kerkhof, Catherine F. Enters-Weijnen, Marianne D. van de Wetering, Wim J.E. Tissing, Matthijs M. Tibben, Hilde Rosing, Arief Lalmohamed, Alwin D.R. Huitema, C. Michel Zwaan*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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Abstract

Purpose: Chemotherapy-induced nausea and vomiting (CINV) are common side effects in pediatric oncology treatment. Besides 5-HT3-antagonists, both dexamethasone and aprepitant are cornerstone drugs in controlling these side effects. Based on results of adult studies, the dexamethasone dose is reduced by 50% when combined with aprepitant, because of a drug-drug interaction, even though data on the interaction in children is lacking. The current study was developed to investigate the effect of aprepitant on dexamethasone clearance (CL) in children, in order to assess if dexamethasone dose reduction for concomitant use of aprepitant is appropriate in the current antiemetic regimen. Methods: In total, 65 children (0.6–17.9 years), receiving intravenous or oral antiemetic therapy (dexamethasone ± aprepitant) as standard of care, were included. 305 dexamethasone plasma concentrations were determined using LC–MS/MS. An integrated dexamethasone and aprepitant pharmacokinetic model was developed using non-linear mixed effects modelling in order to investigate the effect of aprepitant administration on dexamethasone CL. Results: In this population, dexamethasone CL in patients with concomitant administration of aprepitant was reduced by approximately 30% of the uninhibited CL (23.3 L/h (95% confidence interval 20.4–26.0)). This result is not consistent with the results of adult studies (50% reduction). This difference was not age dependent, but might be related to the route of administration of dexamethasone. Future studies are needed to assess the difference in oral/intravenous dexamethasone. Conclusion: When dexamethasone is given intravenously as a component of triple therapy to prevent CINV in children, we advise to reduce the dexamethasone dose by 30% instead of 50%.

Original languageEnglish
Pages (from-to)9991-9999
Number of pages9
JournalSupportive Care in Cancer
Volume30
Issue number12
Early online date26 Oct 2022
DOIs
Publication statusPublished - Dec 2022

Bibliographical note

Funding Information:
This work was supported by Children Cancer-free Foundation (KiKa) project number 320.

Publisher Copyright:
© 2022, The Author(s).

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