Clinical Pharmacometrics, Bayer AG, Leverkusen, Germany.
Department of Pharmaceutical and Medical Chemistry - Clinical Pharmacy, Westfälische Wilhelm-University Münster, Münster, Germany.
J Pharmacokinet Pharmacodyn. 2020 Aug;47(4):341-359. doi: 10.1007/s10928-020-09706-z. Epub 2020 Aug 3.
The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for amoxicillin for non-pregnant, pregnant and postpartum populations by compiling a database incorporating reported changes in the anatomy and physiology throughout the postpartum period. A systematic literature search was conducted to collect data on anatomical and physiological changes in postpartum women. Empirical functions were generated describing the observed changes providing the basis for a generic PBPK framework. The fraction unbound ([Formula: see text]) of predominantly albumin-bound drugs was predicted in postpartum women and compared with experimentally observed values. Finally, a specific amoxicillin PBPK model was newly developed, verified for non-pregnant populations and translated into the third trimester of pregnancy (29.4-36.9 gestational weeks) and early postpartum period (drug administration 1.5-3.8 h after delivery). Pharmacokinetic predictions were evaluated using published clinical data. The literature search yielded 105 studies with 1092 anatomical and physiological data values on 3742 postpartum women which were used to generate various functions describing the observed trends. The [Formula: see text] could be adequately scaled to postpartum women. The pregnancy PBPK model predicted amoxicillin disposition adequately as did the postpartum PBPK model, although clearance was somewhat underestimated. While more research is needed to establish fully verified postpartum PBPK models, this study provides a repository of anatomical and physiological changes in postpartum women that can be applied to future modeling efforts. Ultimately, structural refinement of the developed postpartum PBPK model could be used to investigate drug transfer to the neonate via breast-feeding in silico.
本研究旨在通过整合报告的解剖和生理变化整个产后期间的数据库，为非妊娠、妊娠和产后人群开发一种基于生理的药代动力学 (PBPK) 模型。进行了系统的文献检索，以收集关于产后妇女解剖和生理变化的数据。生成了描述观察到的变化的经验函数，为通用 PBPK 框架提供了基础。预测了主要与白蛋白结合的药物的未结合分数 ([Formula: see text]) 在产后妇女中，并将其与实验观察值进行了比较。最后，新开发了一种特定的阿莫西林 PBPK 模型，在非妊娠人群中进行了验证，并转化为妊娠晚期（29.4-36.9 孕周）和产后早期（给药后 1.5-3.8 小时）。使用已发表的临床数据评估药代动力学预测。文献检索产生了 105 项研究，其中包含 3742 名产后妇女的 1092 个解剖和生理数据值，用于生成描述观察到的趋势的各种函数。[Formula: see text] 可以很好地扩展到产后妇女。妊娠 PBPK 模型和产后 PBPK 模型都能很好地预测阿莫西林的处置，尽管清除率有些低估。虽然需要进一步研究来建立完全验证的产后 PBPK 模型，但本研究提供了一个产后妇女解剖和生理变化的知识库，可用于未来的建模工作。最终，可以通过结构细化开发的产后 PBPK 模型来研究通过母乳喂养在体内向新生儿转移药物。
