Integration of physiological changes during the postpartum period into a PBPK framework and prediction of amoxicillin disposition before and shortly after delivery

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.

Characterization of Plasma Protein Alterations in Pregnant and Postpartum Individuals Living With HIV to Support Physiologically-Based Pharmacokinetic Model Development

“…After delivery, many of the physiologic changes associated with pregnancy take weeks to months to revert to their prepregnancy baseline (17). Studies on antibiotic pharmacology have demonstrated marked alterations in drug pharmacokinetics (PK) between early (2-3 days post-delivery) and late (>4 months postdelivery) postpartum periods (18,19).…”

When special populations intersect with drug–drug interactions: Application of physiologically‐based pharmacokinetic modeling in pregnant populations

“…Clinical studies in pregnant populations often compare pregnant PK with the postpartum period, which may not be the equivalent of the nonpregnant state. Simulations of pregnancy/postpartum ratios improved when we developed postpartum populations based on recently published physiological data for the postpartum period (Dallmann, Himstedt et al., 2020) compared to simulations obtained from using a healthy, nonpregnant female population.…”

“…( Dallmann, Himstedt et al (2020). If postpartum data were not available for a specific parameter, it was assumed to be the same as the nonpregnant population.…”

“…Because these studies compared PK parameters during pregnancy to postpartum periods, postpartum population files at 5 and 9 weeks postpartum were created in SimCyp based on recently published postpartum physiological parameters (Dallmann, Himstedt et al., 2020). Postpartum system parameters used in the model are presented in Table A3.…”

“…• In vitro permeability approach was successful but other calibrators besides highly permeable midazolam should be considered. Amoxicillin (Dallmann, et al, 2020) Inclusion of postpartum population.…”