Integration of physiological changes during the postpartum period into a PBPK framework and prediction of amoxicillin di
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ORIGINAL PAPER
Integration of physiological changes during the postpartum period into a PBPK framework and prediction of amoxicillin disposition before and shortly after delivery Andre´ Dallmann1 Thomas Eissing1
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Anneke Himstedt2,3 • Juri Solodenko1 • Ibrahim Ince1 • Georg Hempel2
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Received: 17 February 2020 / Accepted: 21 July 2020 Ó Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for amoxicillin for nonpregnant, 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 (f u ) 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 f u 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. Keywords PBPK modeling Pregnancy Postpartum Special populations Amoxicillin
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s10928-020-09706-z) contains supplementary material, which is available to authorized users. & Andre´ Dallmann [email protected] 1
Clinical Pharmacometrics, Bayer AG, Leverkusen, Germany
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Department of Pharmaceutical and Medical Chemistry – Clinical Pharmacy, Westfa¨lische Wilhelm-University Mu¨nster, Mu¨nster, Germany
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Department of Clinical Pharmacy, Institute of Pharmacy, University of Hamburg, Hamburg, Germany
During the past years, the efforts to understand the effects of pregnancy on drug pharmacokinetics (PK) have considerably increased. As a result, the literature now abounds with examples of clinically relevant PK changes induced
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