Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Department of Gynecology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
CPT Pharmacometrics Syst Pharmacol. 2023 Dec;12(12):1931-1944. doi: 10.1002/psp4.13043. Epub 2023 Oct 5.
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.
关于接受化疗的母亲母乳喂养时婴儿的暴露和安全性，相关信息有限。虽然定义药物在母乳中的分布对于推断药物暴露很重要，但婴儿的药代动力学也决定了婴儿将在多大程度上暴露于潜在的毒性作用之下。我们旨在通过生理基于药代动力学（PBPK）方法，评估化疗药物进入母乳对婴儿的影响，预测婴儿通过母乳摄入紫杉醇和阿霉素后的全身和局部（肠道）暴露。从文献中扩展了静脉内紫杉醇和阿霉素的全身 PBPK 模型，并增加了口服吸收部分，以能够预测接受紫杉醇或含阿霉素母乳的婴儿。出于安全考虑，探讨了最坏情况。最后，模拟了来自紫杉醇或阿霉素治疗母亲的母乳喂养后婴儿血浆和肠道组织中紫杉醇和阿霉素的暴露情况，并评估了丢弃母乳的策略。预测外周静脉血中峰浓度的第 95 个百分位数分别为紫杉醇和阿霉素的 3.48 和 0.74 nM（治疗期间的 0.4%-1.7%和 0.1%-1.8%）。紫杉醇和阿霉素的肠道暴露分别达到 1.0 和 140 μM 的峰值浓度。在母亲化疗给药后最初 3 天丢弃母乳可进一步降低全身和组织暴露，紫杉醇和阿霉素分别超过 90%和 80%。通过 PBPK 模拟在接受含化疗药物的母乳后婴儿的化疗药物暴露情况表明，应特别监测局部胃肠道不良事件，而全身不良事件则不应预期。
