KU Leuven Drug Delivery and Disposition Lab, Department of Pharmaceutical and Pharmacological Sciences, O&N II Herestraat, 49 3000, Leuven, Belgium.
Neonatal Intensive Care Unit, University Hospitals Leuven, UZ Leuven, Neonatology, Herestraat 49, 3000, Leuven, Belgium; Department of Development and Regeneration, KU Leuven, Belgium.
Biomed Pharmacother. 2021 Apr;136:111038. doi: 10.1016/j.biopha.2020.111038. Epub 2021 Jan 30.
Breastfeeding plays a major role in the health and wellbeing of mother and infant. However, information on the safety of maternal medication during breastfeeding is lacking for most medications. This leads to discontinuation of either breastfeeding or maternal therapy, although many medications are likely to be safe. Since human lactation studies are costly and challenging, validated non-clinical methods would offer an attractive alternative. This review gives an extensive overview of the non-clinical methods (in vitro, in vivo and in silico) to study the transfer of maternal medication into the human breast milk, and subsequent neonatal systemic exposure. Several in vitro models are available, but model characterization, including quantitative medication transport data across the in vitro blood-milk barrier, remains rather limited. Furthermore, animal in vivo models have been used successfully in the past. However, these models don't always mimic human physiology due to species-specific differences. Several efforts have been made to predict medication transfer into the milk based on physicochemical characteristics. However, the role of transporter proteins and several physiological factors (e.g., variable milk lipid content) are not accounted for by these methods. Physiologically-based pharmacokinetic (PBPK) modelling offers a mechanism-oriented strategy with bio-relevance. Recently, lactation PBPK models have been reported for some medications, showing at least the feasibility and value of PBPK modelling to predict transfer of medication into the human milk. However, reliable data as input for PBPK models is often missing. The iterative development of in vitro, animal in vivo and PBPK modelling methods seems to be a promising approach. Human in vitro models will deliver essential data on the transepithelial transport of medication, whereas the combination of animal in vitro and in vivo methods will deliver information to establish accurate in vitro/in vivo extrapolation (IVIVE) algorithms and mechanistic insights. Such a non-clinical platform will be developed and thoroughly evaluated by the Innovative Medicines Initiative ConcePTION.
母乳喂养对母婴的健康和幸福起着重要作用。然而，大多数药物的哺乳期母亲用药安全性信息都缺乏。这导致要么停止母乳喂养，要么停止母亲的治疗，尽管许多药物可能是安全的。由于人体哺乳研究成本高且具有挑战性，因此验证过的非临床方法将是一个有吸引力的替代方法。本综述广泛介绍了研究母体药物进入人乳以及随后新生儿全身暴露的非临床方法（体外、体内和计算）。有几种体外模型可用，但模型特征描述，包括定量药物在体外血乳屏障中的转运数据，仍然相当有限。此外，过去也成功地使用了动物体内模型。然而，由于物种特异性差异，这些模型并不总是能模拟人体生理学。已经做出了一些努力，根据物理化学特性来预测药物向乳汁中的转移。然而，这些方法没有考虑到转运蛋白和一些生理因素（例如，可变的乳脂含量）的作用。基于生理的药代动力学（PBPK）建模提供了一种具有生物相关性的基于机制的策略。最近，已经报道了一些药物的哺乳期 PBPK 模型，至少表明 PBPK 建模预测药物向人乳中的转移是可行且有价值的。然而，PBPK 模型所需的可靠数据通常缺失。体外、动物体内和 PBPK 建模方法的迭代发展似乎是一种很有前途的方法。体外模型将提供关于药物跨上皮转运的重要数据，而动物体外和体内方法的结合将提供信息，以建立准确的体外/体内外推（IVIVE）算法和机制见解。这样的非临床平台将由创新药物倡议 ConcePTION 开发并进行彻底评估。
