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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., (© 2023 The Authors. CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

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. [ABSTRACT FROM AUTHOR]

Little is known about infant's safety of chemotherapy during breastfeeding where evidence is limited to a few case reports. This lack of knowledge has led to a general tendency to advise against breastfeeding during cytotoxic therapy despite the overwhelming benefits that breastfeeding offers to both the mothers and their children. In this case series, the presence of five chemotherapies in breast milk was determined. The aim was to obtain insight into the presence of these drugs in breast milk to inform and help clinicians in making informed decisions for women who want to breastfeed. Three patients collected 24‐hour samples of breast milk every day for 1, 2, or 3 weeks after chemotherapy, 210 in total. After determination of drug concentrations, the infant daily dose, relative daily infant dose (RID%) and cumulative RID were calculated. Cumulative RIDs in patients varied from 10% to values lower than 1%. Rich data allowed us to design a table which gives predictions on the amount of days that breast milk has to be discarded to reach cumulative RIDs below 5, 1, and 0.1% for each compound. For cyclophosphamide, paclitaxel, and carboplatin, cumulative RIDs below 1 or 0.1% are reached if breast milk is discarded for 1–3 days after administration. This might suggest that breastfeeding in between cycles is an option. However, other pharmacological parameters should also be taken into consideration. For doxorubicin, also the levels of the active metabolite doxorubicinol need quantification. Similarly, breastfeeding during treatment with cisplatin might give substantial exposure and we advise caution. [ABSTRACT FROM AUTHOR]

ModraPac001 (MP1) and ModraPac005 (MP5) are novel oral paclitaxel formulations that are coadministered with the cytochrome P450 3A4 inhibitor ritonavir (r), enabling daily low‐dose metronomic (LDM) treatment. The primary aim of this study was to determine the safety, pharmacokinetics and maximum tolerated dose (MTD) of MP1/r and MP5/r. The second aim was to establish the recommended phase 2 dose (RP2D) as LDM treatment. This was an open‐label phase 1 trial. Patients with advanced solid tumors were enrolled according to a classical 3+3 design. After initial employment of the MP1 capsule, the MP5 tablet was introduced. Safety was assessed using the Common Terminology Criteria for Adverse Events version 4.02. Pharmacokinetic sampling was performed on days 1, 2, 8, and 22 for determination of paclitaxel and ritonavir plasma concentrations. In this study, 37 patients were treated with up to twice‐daily 30‐mg paclitaxel combined with twice‐daily 100‐mg ritonavir (MP5/r 30‐30/100‐100) in 9 dose levels. Dose‐limiting toxicities were nausea, (febrile) neutropenia, dehydration and vomiting. At the MTD/RP2D of MP5/r 20‐20/100‐100, the maximum paclitaxel plasma concentration and area under the concentration‐time curve until 24 hours were 34.6 ng/mL (coefficient of variation, 79%) and 255 ng • h/mL (coefficient of variation, 62%), respectively. Stable disease was observed as best response in 15 of 31 evaluable patients. Based on these results, LDM therapy with oral paclitaxel coadministrated with ritonavir was considered feasible and safe. The MTD and RP2D were determined as MP5/r 20‐20/100‐100. Further clinical development of MP5/r as an LDM concept, including potential combination treatment, is warranted. [ABSTRACT FROM AUTHOR]