Physiologically Based Pharmacokinetic Models to Predict Maternal Pharmacokinetics and Fetal Exposure to Emtricitabine and Acyclovir

Liu, Xiaomei I.; Momper, Jeremiah D.; Rakhmanina, Natella; Anker, John N. van den; Green, Dionna J.; Burckart, Gilbert J.; Best, Brookie M.; Mirochnick, Mark; Capparelli, Edmund V.; Dallmann, André

doi:10.1002/jcph.1515

Cited by 39 publications

(33 citation statements)

References 58 publications

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“…This was motivated by the fact that the pregnant PBPK model parameterization served as starting point for the physiological alterations during the postpartum period thereby allowing an evaluation of these physiological parameters prior to the onset of labor. Similar to previous pregnancy PBPK models for predominantly renally cleared drugs [22,23], the herein presented model predicted amoxicillin PK adequately which further increases the credibility of the pregnancy PBPK model.…”

Section: Discussionsupporting

confidence: 78%

“…Previously, a pregnancy PBPK model has been developed in the OSP software package and evaluated for various drugs [22,23,[33][34][35]; amoxicillin is not part of the previously modeled drugs. Here, this generic model was applied to develop an additional substance model for amoxicillin to predict the disposition of intravenously administered amoxicillin prior to child birth.…”

Section: Pregnancy Pbpk Modelmentioning

confidence: 99%

“…Although multiple pregnancy PBPK models have been reported for predominantly renally cleared drugs (e.g. cefazolin, cefradine, and cefuroxime [22] as well as acyclovir and emtricitabine [23]), amoxicillin has not been part of the modelled compounds. To develop a postpartum PBPK model, the scientific literature was searched for information on changes in anatomical and physiological parameters during the postpartum period.…”

Section: Introductionmentioning

confidence: 99%

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

Dallmann

Himstedt

Solodenko

et al. 2020

J Pharmacokinet Pharmacodyn

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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.

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Section: Discussionsupporting

confidence: 78%

Section: Pregnancy Pbpk Modelmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Dallmann

Himstedt

Solodenko

et al. 2020

J Pharmacokinet Pharmacodyn

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“…While D pl was not a sensitive parameter for acetaminophen, future studies could test high permeability compounds with high K f,m values to generate more knowledge about the validity of predicting D pl via different approaches. Overall, the results of the comparison of the different approaches for estimating placental transfer are in line with a recently published study on emtricitabine and acyclovir that demonstrated that fetal exposure can be adequately predicted when placental transfer is informed either by the ex vivo cotyledon experiment or by the approach by Liu et al [54]. Still, more research on other drugs with a K f,m approximating 1.0 and high permeability is clearly needed to further build confidence.…”

Section: Discussionsupporting

confidence: 74%

Integration of Placental Transfer in a Fetal–Maternal Physiologically Based Pharmacokinetic Model to Characterize Acetaminophen Exposure and Metabolic Clearance in the Fetus

et al. 2020

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Background and Objective Although acetaminophen is frequently used during pregnancy, little is known about fetal acetaminophen pharmacokinetics. Acetaminophen safety evaluation has typically focused on hepatotoxicity, while other events (fetal ductal closure/constriction) are also relevant. We aimed to develop a fetal-maternal physiologically based pharmacokinetic (PBPK) model (f-m PBPK) to quantitatively predict placental acetaminophen transfer, characterize fetal acetaminophen exposure, and quantify the contributions of specific clearance pathways in the term fetus. Methods An acetaminophen pregnancy PBPK model was extended with a compartment representing the fetal liver, which included maturation of relevant enzymes. Different approaches to describe placental transfer were evaluated (ex vivo cotyledon perfusion experiments, placental transfer prediction based on Caco-2 cell permeability or physicochemical properties [MoBi ® ]). Predicted maternal and fetal acetaminophen profiles were compared with in vivo observations. Results Tested approaches to predict placental transfer showed comparable performance, although the ex vivo approach showed highest prediction accuracy. Acetaminophen exposure in maternal venous blood was similar to fetal venous umbilical cord blood. Prediction of fetal acetaminophen clearance indicated that the median molar dose fraction converted to acetaminophen-sulphate and N-acetyl-p-benzoquinone imine was 0.8% and 0.06%, respectively. The predicted mean acetaminophen concentration in the arterial umbilical cord blood was 3.6 mg/L. Conclusion The median dose fraction of acetaminophen converted to its metabolites in the term fetus was predicted. The various placental transfer approaches supported the development of a generic f-m PBPK model incorporating in vivo placental drug transfer. The predicted arterial umbilical cord acetaminophen concentration was far below the suggested postnatal threshold (24.47 mg/L) for ductal closure.

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“…9 Pharmacokinetic (PK) models have been constructed to predict fetal exposure using transplacental transfer parameters obtained from ex vivo human placental perfusion systems for various drugs, including tenofovir, emtricitabine (De Sousa Mendes et al, 2016), nevirapine (De Sousa Mendes et al, 2017), and acyclovir (Liu et al, 2019) in closed systems, paroxetine, antipyrine (Nagai et al, 2013), fluvoxamine (Matsuoka et al, 2017), and ketoprofen (Tanaka et al, 2017) in open systems, and darunavir (Schalkwijk et al, 2018) in a hybrid system (closed-open system). However, in those studies, the transplacental transfer of test drugs was mostly mediated by passive diffusion, and thus the contribution of transporter(s) to the clearance was not estimated.…”

Section: Downloaded Frommentioning

confidence: 99%

Development of a Pharmacokinetic Model of Transplacental Transfer of Metformin to Predict In Vivo Fetal Exposure

et al. 2020

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Physiologically Based Pharmacokinetic Models to Predict Maternal Pharmacokinetics and Fetal Exposure to Emtricitabine and Acyclovir

Abstract: Pregnancy is associated with physiological changes that may impact drug pharmacokinetics (PK). The goals of this study were to build maternal-fetal physiologically based pharmacokinetic (PBPK) models for acyclovir and emtricitabine, 2 anti(retro)viral drugs with active renal net

Cited by 39 publications

References 58 publications

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

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

Integration of Placental Transfer in a Fetal–Maternal Physiologically Based Pharmacokinetic Model to Characterize Acetaminophen Exposure and Metabolic Clearance in the Fetus

Development of a Pharmacokinetic Model of Transplacental Transfer of Metformin to Predict In Vivo Fetal Exposure

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