Sychterz Caroline, Shen Hong, Zhang Yueping, Sinz Michael, Rostami-Hodjegan Amin, Schmidt Brian J, Gaohua Lu, Galetin Aleksandra
Division of Pharmacy and Optometry, Centre for Applied Pharmacokinetic Research, School of Health Sciences, University of Manchester, Manchester, UK.
Bristol Myers Squibb, Princeton, New Jersey, USA.
CPT Pharmacometrics Syst Pharmacol. 2024 Nov;13(11):1856-1869. doi: 10.1002/psp4.13243. Epub 2024 Sep 18.
Breastfeeding is the most complete nutritional method of feeding infants, but several impediments affect the decision to breastfeed, including questions of drug safety for medications needed during lactation. Despite recent FDA guidance, few labels provide clear dosing advice during lactation. Physiologically based pharmacokinetic modeling (PBPK) is well suited to mechanistically explore pharmacokinetics and dosing paradigms to fill gaps in the absence of extensive clinical studies and complement existing real-world data. For lactation-focused PBPK (Lact-PBPK) models, information on system parameters (e.g., expression of drug transporters in mammary epithelial cells) is sparse. The breast cancer resistance protein (BCRP) is expressed on the apical side of mammary epithelial cells where it actively transports drugs/substrates into milk (reported milk: plasma ratios range from 2 to 20). A critical review of BCRP and its role in lactation was conducted. Longitudinal changes in BCRP mRNA expression have been identified in women with a maximum reached around 5 months postpartum. Limited data are available on the ontogeny of BCRP in infant intestine; however, data indicate lower BCRP abundance in infants compared to adults. Current status of incorporation of drug transporter information in Lact-PBPK models to predict active secretion of drugs into breast milk and consequential exposure of breast-fed infants is discussed. In addition, this review highlights novel clinical tools for evaluation of BCRP activity, namely a potential non-invasive BCRP biomarker (riboflavin) and liquid biopsy that could be used to quantitatively elucidate the role of this transporter without the need for administration of drugs and to inform Lact-PBPK models.
母乳喂养是喂养婴儿最完善的营养方式，但有几个障碍影响母乳喂养的决定，包括哺乳期所需药物的安全性问题。尽管美国食品药品监督管理局（FDA）近期发布了指南，但很少有药品标签提供哺乳期的明确给药建议。基于生理的药代动力学建模（PBPK）非常适合从机制上探索药代动力学和给药模式，以填补缺乏广泛临床研究的空白，并补充现有的实际数据。对于以哺乳期为重点的PBPK（Lact-PBPK）模型，系统参数信息（如乳腺上皮细胞中药物转运体的表达）很少。乳腺癌耐药蛋白（BCRP）在乳腺上皮细胞的顶端表达，它在那里将药物/底物主动转运到乳汁中（报道的乳汁与血浆的比率范围为2至20）。对BCRP及其在哺乳期的作用进行了批判性综述。已确定产后约5个月左右达到最大值的女性中BCRP mRNA表达的纵向变化。关于婴儿肠道中BCRP个体发育的可用数据有限；然而，数据表明婴儿体内的BCRP丰度低于成年人。讨论了将药物转运体信息纳入Lact-PBPK模型以预测药物向母乳中的主动分泌以及母乳喂养婴儿相应暴露情况的现状。此外，本综述强调了评估BCRP活性的新型临床工具，即一种潜在的非侵入性BCRP生物标志物（核黄素）和液体活检，它们可用于定量阐明该转运体的作用，而无需给药，并为Lact-PBPK模型提供信息。
