Fetal Physiologically Based Pharmacokinetic Models: Systems Information on the Growth and Composition of Fetal Organs

Abduljalil, Khaled; Jamei, Masoud; Johnson, Trevor N.

doi:10.1007/s40262-018-0685-y

Cited by 39 publications

(35 citation statements)

References 170 publications

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“…Apart from the explicit integration of placental transporters, these models may also benefit from finer representation of fetal physiology. Recently, several repositories have been published that review physiological changes in the fetus, such as organ growth, change in blood flow rates, tissue composition, and drug‐binding protein concentrations . In addition, drug transfer may also be influenced by the pH difference between the fetal and maternal blood.…”

Section: Models For Placental Drug Transfermentioning

confidence: 99%

“…Recently, several repositories have been published that review physiological changes in the fetus, such as organ growth, change in blood flow rates, tissue composition, and drug-binding protein concentrations. [98][99][100] In addition, drug transfer may also be influenced by the pH difference between the fetal and maternal blood. Under normal conditions, the pH of the umbilical cord blood is about 0.1 log units lower than that of the maternal blood, which can, in principle, lead to an increased fetal/maternal concentration ratio of weakly basic drugs.…”

Section: Ex Vivo Cotyledon Perfusion Experimentsmentioning

confidence: 99%

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Drug Transporters Expressed in the Human Placenta and Models for Studying Maternal‐Fetal Drug Transfer

Dallmann

Liu

Burckart

et al. 2019

The Journal of Clinical Pharma

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Tremendous efforts have been directed to investigate the ontogeny of drug transporters in fetuses, neonates, infants, and children based on their importance for understanding drug pharmacokinetics. During development (ie, in the fetus and newborn infant), there is special interest in transporters expressed in the placenta that modulate placental drug transfer. Many of these transporters can decrease or increase drug concentrations in the fetus and at birth, stressing the relevance of elucidating expression in the placenta and potential gestational age‐dependent changes therein. Hence, the main objective of this review was to summarize the current knowledge about expression and ontogeny of transporters in the human placenta in healthy pregnant women. In addition, various in vitro, ex vivo, and in silico models that can be used to investigate placental drug transfer, namely, placental cancer cell lines, ex vivo cotyledon perfusion experiments, and physiologically based pharmacokinetic (PBPK) models, are discussed together with their advantages and shortcomings. A particular focus was placed on PBPK models because these models can integrate different types of information, such as expression data, ontogeny information, and observations obtained from the ex vivo cotyledon perfusion experiment. Such a mechanistic modeling framework may leverage the available information and ultimately help to improve knowledge about the adequacy and safety of pharmacotherapy in pregnant women and their fetuses.

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Section: Models For Placental Drug Transfermentioning

confidence: 99%

Section: Ex Vivo Cotyledon Perfusion Experimentsmentioning

confidence: 99%

Drug Transporters Expressed in the Human Placenta and Models for Studying Maternal‐Fetal Drug Transfer

Dallmann

Liu

Burckart

et al. 2019

The Journal of Clinical Pharma

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“…The apparently poor fit of the model of Abduljalil et al [31] to their own curated data set is probably 775 due to precision-related errors -they only reported the leading coefficient of their polynomial model to 776 one significant figure. 31], and the curated summary data [31] are shown in Figure 18. 31], and the curated summary data [31] are shown in Figure 19.…”

mentioning

confidence: 93%

“…31], and the curated summary data [31] are shown in Figure 18. 31], and the curated summary data [31] are shown in Figure 19. 820 821 31], and the curated summary data [31] are shown in Figure 20.…”

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confidence: 99%

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Empirical Models for Anatomical and Physiological Changes in a Human Mother and Fetus During Pregnancy and Gestation

Kapraun

Wambaugh

Setzer

et al. 2018

Preprint

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12Many parameters treated as constants in traditional physiologically based pharmacokinetic models must 13 be formulated as time-varying quantities when modeling pregnancy and gestation due to the dramatic 14 physiological and anatomical changes that occur during this period. While several collections of 15 empirical models for such parameters have been published, each has shortcomings. We sought to create 16 a repository of empirical models for tissue volumes, blood flow rates, and other quantities that undergo 17 substantial changes in a human mother and her fetus during the time between conception and birth, 18 and to address deficiencies with similar, previously published repositories. We used maximum likelihood 19 estimation to calibrate various models for the time-varying quantities of interest, and then used the 20 Akaike information criterion to select an optimal model for each quantity. For quantities of interest for 42 physiological changes that occur in a human mother and fetus during pregnancy and gestation. We 43 evaluated and selected models by applying a consistent statistical technique, and where possible, we 44 compared results produced by our models to those produced by previously-published models. The 45 collection of pregnancy parameter models presented here represents the most comprehensive such 46 collection to date. 48Human health chemical risk assessments frequently consider pregnant women as a subpopulation of 49 interest based on the relatively high exposure rates and/or susceptibility of this group to various 50 compounds [1,2]. Unfortunately, pregnant women are generally underrepresented in pharmaceutical 51 clinical studies [3] and non-therapeutic chemicals are rarely studied in humans at any life-stage [4][5][6]. In 52 order to assess the risk posed by a chemical, pharmacokinetic (PK) modeling can be used to relate 53 chemical exposure to potential toxicity in tissues [7]. PK models describe chemical absorption, 54 distribution, metabolism, and elimination by the body [8,9]. Furthermore, such models allow one to 55 quantify the tissue concentrations resulting from external doses, whether they are controlled (e.g., 56doses administered in a clinical trial or animal toxicity study [10]) or uncontrolled (e.g., through complex 57 environmental exposures [11]). 58During gestation there are windows of toxic susceptibility during which chemical insults may induce life-59 long adverse effects [2,9,[12][13][14]. Mathematical PK models provide a means for predicting fetal tissue 60 exposures to chemicals [12,15]. Given that PK data in pregnant women and in utero infants are 61 unavailable for most chemicals, models are needed to estimate doses of concern based on data 62 collected for non-pregnant adults or from animals [12]. Physiologically based PK (PBPK) models offer an 63 attractive option for extrapolating information in applications such as human health risk assessments 64 [16-18]. Furthermore, PBPK models can be used to understand and potentially replace some of the 65 default uncertain...

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Pharmacokinetics of Drugs in Pregnancy and Lactation

Steinberg

2019

Cardiac Problems in Pregnancy, 4th Edition

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Fetal Physiologically Based Pharmacokinetic Models: Systems Information on the Growth and Composition of Fetal Organs

Cited by 39 publications

References 170 publications

Drug Transporters Expressed in the Human Placenta and Models for Studying Maternal‐Fetal Drug Transfer

Drug Transporters Expressed in the Human Placenta and Models for Studying Maternal‐Fetal Drug Transfer

Empirical Models for Anatomical and Physiological Changes in a Human Mother and Fetus During Pregnancy and Gestation

Pharmacokinetics of Drugs in Pregnancy and Lactation

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