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. 2023 Jul;62(7):969-980.
doi: 10.1007/s40262-023-01251-5. Epub 2023 May 8.

Predicting Chemotherapy Distribution into Breast Milk for Breastfeeding Women Using a Population Pharmacokinetic Approach

David Damoiseaux  1 , Daniel Centanni  2 , Jos H Beijnen  2   3 , Frédéric Amant  4   5 , Alwin D R Huitema  2   6   7 , Thomas P C Dorlo  2   8
Affiliations

Predicting Chemotherapy Distribution into Breast Milk for Breastfeeding Women Using a Population Pharmacokinetic Approach

David Damoiseaux et al. Clin Pharmacokinet. 2023 Jul.

Abstract

Background and objective: Information on the distribution of chemotherapeutic drugs to breast milk is scarce, and reports are limited to small sample sizes. Anecdotal pharmacokinetic data have typically been acquired from lactating but non-breastfeeding patients who collect breast milk by means of an expression pump, which might not necessarily be representative for a breastfeeding population due to differences in milk production. Consequently, little is known about the variability of chemotherapy distribution to breast milk and the effect of milk production on the distribution of chemotherapy to breast milk. Our aim was to predict chemotherapy distribution to breast milk in a more realistic breastfeeding population and evaluate the effect of discarding breast milk on the potential chemotherapy exposure in infants.

Methods: We developed a population pharmacokinetic model that described the breast milk production and the chemotherapy distribution to breast milk of a non-breastfeeding population, linked it to plasma pharmacokinetics, and extrapolated this to a breastfeeding population.

Results: We found that cumulative relative infant doses (RID) were higher than 10% for cyclophosphamide and doxorubicin and approximately 1% for paclitaxel. Simulations allowed us to predict the cumulative RID and its variability in the population for patients with different milk productions and the amount of breast milk that has to be discarded to reach cumulative RIDs below 1%, 0.1%, and 0.01%. Discarding 1-2, 3-6, and 0-1 days of breast milk (depending on the milk production of the patient) resulted in cumulative RID below 1% for cyclophosphamide, doxorubicin, and paclitaxel, respectively.

Conclusion: Our results may help clinicians to derive the optimal breast milk discarding strategy for an individual patient that wants to breastfeed during chemotherapy and minimize chemotherapy exposure in their infants.

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Conflict of interest statement

All authors declared no competing interests for this work.

Figures

Fig. 1
Fig. 1
The individual total daily (red) and separately sampled (blue) volumes (in mL) of breast milk over time (in days) for patients 1, 2, and 3. Trend lines represent the decline in daily milk production over time until a steady-state milk production is reached (if applicable) and vertical lines represent the start of a new chemotherapy combination. Patients 2 and 3 only received one combination of chemotherapies
Fig. 2
Fig. 2
Predictions of the first and fourth week of sampled breast milk volumes by A the milk production model and B the milk production model with separately estimated fixed effects for each patient. We chose to only show the predictions of the first and fourth week to keep the figure comprehensive and to give an idea of the model performance. Red triangles represent the observations, black lines represent the median predictions, and the blue areas represent the 80% prediction intervals. Predictions consisted of 250 simulations each
Fig. 3
Fig. 3
Simulated median concentrations of cyclophosphamide, doxorubicin, and paclitaxel in breast milk over 3 days, with 80% prediction interval in blue. A total of 500 simulations were performed for a virtual patient with an average steady-state milk production of 32.8 mL/h and an average maximal breast capacity of 358 mL, expressing breast milk seven times between 6 AM and 6 PM and four times between 6 PM and 6 AM. The patient was administered an intravenous dose of 600 mg/m2, 60 mg/m2, and 80 mg/m2 with an infusion time of 2 h, 2 h, and 3 h for cyclophosphamide, doxorubicin, and paclitaxel, respectively (patient body surface area of 1.7 m2)
Fig. 4
Fig. 4
Simulated cumulative RIDs in breast milk for cyclophosphamide, doxorubicin, and paclitaxel for a virtual patient with an average steady-state milk production of 32.8 mL/h and an average maximal breast capacity of 358 mL with a different amount of days of discarded breast milk. The amount of discarded days of breast milk was based on the amount of days in a cycle of chemotherapy, 14 days for cyclophosphamide and doxorubicin, and 7 days for paclitaxel. Box plots in blue represent the cumulative RIDs in the total volume of milk produced in 1 day, and red represents cumulative RIDs in the volume of milk that is consumed by the average infant in 1 day
Fig. 5
Fig. 5
A The milk production for each simulated individual, B the cumulative RID for each drug and individual with 95% confidence interval, and C the number of days after the start of maternal chemotherapy administration, for which breast milk has to be discarded to reach a cumulative RID below 1%, 0.1%, and 0.01% (and 95% prediction interval) for the different compounds, with the assumption that the infant drinks all the available milk produced by the nine IDs with corresponding milk production parameters (C). Cumulative RID is calculated until the end of a cycle, 7 days after administration for paclitaxel, 14 days after administration for cyclophosphamide and doxorubicin. Missing averages (dots) and error bars that reach 14 days for doxorubicin and 7 days for paclitaxel indicate that the cumulative RID did not reach this value (< 1%, 0.1%, or 0.01%) within the duration of a cycle (C). The different IDs originate from Table 1. RID relative infant dose
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