Minimal <scp>physiologically‐based</scp> hybrid model of pharmacokinetics in pregnant women: Application to antenatal corticosteroids

Krzyzanski, Wojciech; Milad, Mark A.; Jobe, Alan H.; Jusko, William J.

doi:10.1002/psp4.12899

Cited by 8 publications

(3 citation statements)

References 44 publications

(88 reference statements)

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“…Both the maternal postpartum and pregnancy PK data were accurately predicted for MET and MTD without any clearance model parameters adjustments (considering CYP polymorphism in the predictions). Recent PBPK models focusing on similar compounds have used a similar strategy [ 13 , 15 , 46 , 47 , 48 , 49 ]. Therefore, it is plausible that the relationships describing the CYP enzymes’ expression level during pregnancy are sufficient to predict the maternal PK using a PBPK model at different stages of pregnancy.…”

Section: Discussionmentioning

confidence: 99%

PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Metabolism in Pregnant Subjects and Fetuses

Le Merdy,

Szeto,

Perrier

et al. 2024

Pharmaceutics

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This study aimed to develop a physiologically based pharmacokinetic (PBPK) model that simulates metabolically cleared compounds’ pharmacokinetics (PK) in pregnant subjects and fetuses. This model accounts for the differences in tissue sizes, blood flow rates, enzyme expression levels, plasma protein binding, and other physiological factors affecting the drugs’ PK in both the pregnant woman and the fetus. The PBPKPlus™ module in GastroPlus® was used to model the PK of metoprolol, midazolam, and metronidazole for both non-pregnant and pregnant groups. For each of the three compounds, the model was first developed and validated against PK data in healthy non-pregnant volunteers and then applied to predict the PK in the pregnant groups. The model accurately described the PK in both the non-pregnant and pregnant groups and explained well the differences in the plasma concentration due to pregnancy. When available, the fetal plasma concentration, placenta, and fetal tissue concentrations were also predicted reasonably well at different stages of pregnancy. The work described the use of a PBPK approach for drug development and demonstrates the ability to predict differences in PK in pregnant subjects and fetal exposure for metabolically cleared compounds.

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Section: Discussionmentioning

confidence: 99%

PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Metabolism in Pregnant Subjects and Fetuses

Le Merdy,

Szeto,

Perrier

et al. 2024

Pharmaceutics

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“…Taken together, these animal and human studies suggest that a fetal steroid concentration of 1-4 ng/ml could bring about a lung maturational response. Pharmacokinetic modelling of conventionally used ACS regimens suggest that fetal steroid levels are approximately 3-4 times higher [22]. The duration of fetal exposure to ACS at adequate levels is also critical to the maturational response.…”

Section: Evaluating a Lower Dose Of Acsmentioning

confidence: 99%

The World Health Organization Antenatal CorTicosteroids for Improving Outcomes in preterm Newborns (ACTION-III) Trial: study protocol for a multi-country, multi-centre, double-blind, three-arm, placebo-controlled, individually randomized trial of antenatal corticosteroids for women at high probability of late preterm birth in hospitals in low- and middle-income countries

Adegboyega,

Adejuyigbe,

Adesina

et al. 2023

Preprint

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Background: Preterm birth complications are the leading cause of newborn and under-5 mortality. Over 85% of all preterm births occur in the late preterm period i.e., between 34 and <37 weeks of gestation. Antenatal corticosteroids (ACS) prevent mortality and respiratory morbidity when administered to women at high risk of an early preterm birth i.e. < 34 weeks’ gestation. However, the benefits and risks of ACS in the late preterm period are less clear; both guidelines and practices vary between settings. Emerging evidence suggests that the benefits of ACS may be achievable at lower doses than presently used. This trial aims to determine the efficacy and safety of two ACS regimens compared to placebo, when given to women with a high probability of late preterm birth, in hospitals in low-middle income countries (LMICs). Methods: WHO ACTION III trial is a parallel-group, three-arm, individually randomized, double-blind, placebo-controlled trial of two ACS regimens: dexamethasone phosphate 4x6 mg q12h or betamethasone phosphate 4x2 mg q 12h. The trial is being conducted across seven sites in five countries- Bangladesh, India, Kenya, Nigeria and Pakistan. Eligible women are those with a gestational age between 34 weeks 0 days and 36 weeks 5 days, who have a high probability of preterm birth in next 12 hours to 7 days (up to 36 weeks 6 days gestation). The primary outcome is a composite of stillbirth or neonatal death within 72 hours of birth, or use of newborn respiratory support within 72 hours of birth or prior to discharge from hospital, whichever is earlier. Secondary outcomes include safety and health utilization measures for both women and newborns The sample size is 13,500 women. Discussion: This trial will evaluate the benefits and possible harms of ACS when used in women likely to have a late preterm birth. It will also evaluate a lower-dose ACS regimen based on literature from pharmacokinetic studies. The results of this trial will provide robust critical evidence on the safe and appropriate use of ACS in the late preterm period internationally. Trial registration: ISRCTN11434567. Registered on 7 June 2021; https://doi.org/10.1186/ISRCTN11434567.

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“…On one hand, it is challenging to accurately describe the dose-fetal exposure relationship for DEX. Currently, most DEX pharmacokinetic (PK) studies primarily concentrate on simulating maternal blood levels. − Nevertheless, there remains substantial variability in predicting fetal blood drug concentrations . On the other hand, establishing the fetal exposure-effect relationship for DEX is also challenging.…”

mentioning

confidence: 99%

Systematic Quantitative Analysis of Fetal Dexamethasone Exposure and Fetal Lung Maturation in Pregnant Animals: Model Informed Dexamethasone Precision Dose Study

Song,

Wang

et al. 2024

ACS Pharmacol. Transl. Sci.

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Dexamethasone (DEX) was applied in neonatal respiratory distress syndrome treatment of pregnant women. We established a pharmacokinetics (PK)/pharmacodynamics(PD)/end point model of pregnant animals based on published data and then extrapolated to simulate fetal exposure and lung maturation in pregnant women. We first established the PK/PD/end point model for DEX in pregnant sheep. We considered the competitive effect of cortisol (Cort) and DEX binding with glucocorticoid receptor and then used the indirect response model to describe disaturated-phosphatidylcholine (DSPC) dynamics. Based on that, we established a regression relationship between DSPC and fetal lung volume (V40). We then extrapolated the PD/end point model of pregnant sheep to pregnant monkeys by corrected stages of morphologic lung maturation in two species. Finally, we utilized the interspecies extrapolation strategy to simulate fetal exposure (AUC0–48h) and V40 relationship in pregnant women. The current model could well describe the maternal-fetal PK of DEX in pregnant animals. Simulated DEX AUC0–24h values of the umbilical venous to maternal plasma ratio in pregnant sheep and monkeys were 0.31 and 0.27, respectively. The simulated Cort curve and V40 in pregnant sheep closely matched the observed data within a 2-fold range. For pregnant monkeys, model-simulated V40 were well fitted with external verification data, which showed good interspecies extrapolation performance. Finally, we simulated fetal exposure–response relationship in pregnant women, which indicated that the fetal AUC0–48h of DEX should not be less than 300 and 100 ng/mL·hr at GW28 and GW34 to ensure fetal lung maturity. The current model preliminarily provided support for clinical DEX dose optimization.

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Minimal physiologically‐based hybrid model of pharmacokinetics in pregnant women: Application to antenatal corticosteroids

Cited by 8 publications

References 44 publications

PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Metabolism in Pregnant Subjects and Fetuses

PBPK Modeling Approach to Predict the Behavior of Drugs Cleared by Metabolism in Pregnant Subjects and Fetuses

Systematic Quantitative Analysis of Fetal Dexamethasone Exposure and Fetal Lung Maturation in Pregnant Animals: Model Informed Dexamethasone Precision Dose Study

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