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Lookup NU author(s): Dr Shelby BarnettORCiD, Professor Gareth Veal
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).
© 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.Limited information is available concerning infant exposure and safety when breastfed by mothers receiving chemotherapy. Whereas defining distribution to breast milk is important to infer drug exposure, infant pharmacokinetics also determine to what extent the infant will be exposed to potential toxic effects. We aimed to assess the impact of chemotherapy containing breast milk on infants by predicting systemic and local (intestinal) exposure of paclitaxel and doxorubicin in infants through breast milk using a physiologically-based pharmacokinetic (PBPK) approach. Whole-body PBPK models of i.v. paclitaxel and doxorubicin were extended from the literature, with an oral absorption component to enable predictions in infants receiving paclitaxel or doxorubicin-containing breast milk. For safety considerations, worst-case scenarios were explored. Finally, paclitaxel and doxorubicin exposures in plasma and intestinal tissue of infants following feeding of breast milk from paclitaxel- or doxorubicin-treated mothers were simulated and breast milk discarding strategies were evaluated. The upper 95th percentile of the predicted peak concentrations in peripheral venous blood were 3.48 and 0.74 nM (0.4%–1.7% and 0.1%–1.8% of on-treatment) for paclitaxel and doxorubicin, respectively. Intestinal exposure reached peak concentrations of 1.0 and 140 μM for paclitaxel and doxorubicin, respectively. Discarding breast milk for the first 3 days after maternal chemotherapy administration reduced systemic and tissue exposures even further, to over 90% and 80% for paclitaxel and doxorubicin, respectively. PBPK simulations of chemotherapy exposure in infants after breastfeeding with chemotherapy containing breast milk suggest that particularly local gastrointestinal adverse events should be monitored, whereas systemic adverse events are not expected.
Author(s): Damoiseaux D, Amant F, Beijnen JH, Barnett S, Veal GJ, Huitema ADR, Dorlo TPC
Publication type: Article
Publication status: Published
Journal: CPT: Pharmacometrics and Systems Pharmacology
Year: 2023
Volume: 12
Issue: 12
Pages: 1931-1944
Print publication date: 01/12/2023
Online publication date: 05/10/2023
Acceptance date: 29/08/2023
Date deposited: 31/10/2023
ISSN (electronic): 2163-8306
Publisher: American Society for Clinical Pharmacology and Therapeutics
URL: https://doi.org/10.1002/psp4.13043
DOI: 10.1002/psp4.13043
Data Access Statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.
PubMed id: 37798909
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