Evaluation of Maternal Drug Exposure Following the Administration of Antenatal Corticosteroids During Late Pregnancy Using Physiologically‐Based Pharmacokinetic Modeling

Ke, Alice Ban; Milad, Mark A.

doi:10.1002/cpt.1438

Cited by 30 publications

(58 citation statements)

References 38 publications

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“…In conclusion, oral ACS treatments are feasible. Dosing can be adjusted based on pharmacokinetics to achieve fetal exposures that avoid high and unnecessary fetal plasma corticosteroid levels, as demonstrated for intramuscular treatments [33]. Reliable oral dosing may depend on variable such as recent food consumption, maternal weight which will need to be explored clinically.…”

Section: Discussionmentioning

confidence: 99%

Oral dosing for antenatal corticosteroids in the Rhesus macaque

Schmidt

Kemp

Milad³

et al. 2019

PLoS ONE

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Antenatal corticosteroids (ACS) are standard of care for women at risk of preterm delivery, although choice of drug, dose or route have not been systematically evaluated. Further, ACS are infrequently used in low resource environments where most of the mortality from prematurity occurs. We report proof of principle experiments to test betamethasone-phosphate (Beta-P) or dexamethasone-phosphate (Dex-P) given orally in comparison to the clinical treatment with the intramuscular combination drug beta-phosphate plus beta-acetate in a Rhesus Macaque model. First, we performed pharmacokinetic studies in non-pregnant monkeys to compare blood levels of the steroids using oral dosing with Beta-P, Dex-P and an effective maternal intramuscular dose of the beta-acetate component of the clinical treatment. We then evaluated maternal and fetal blood steroid levels with limited fetal sampling under ultrasound guidance in pregnant macaques. We found that oral Beta is more slowly cleared from plasma than oral Dex. The blood levels of both drugs were lower in maternal plasma of pregnant than in non-pregnant macaques. Using the pharmacokinetic data, we treated groups of 6–8 pregnant monkeys with oral Beta-P, oral Dex-P, or the maternal intramuscular clinical treatment and saline controls and measured pressure-volume curves to assess corticosteroid effects on lung maturation at 5d. Oral Beta-P improved the pressure-volume curves similarly to the clinical treatment. Oral Dex-P gave more variable and nonsignificant responses. We then compared gene expression in the fetal lung, liver and hippocampus between oral Beta-P and the clinical treatment by RNA-sequencing. The transcriptomes were largely similar with small gene expression differences in the lung and liver, and no differences in the hippocampus between the groups. As proof of principle, ACS therapy can be effective using inexpensive and widely available oral drugs. Clinical dosing strategies must carefully consider the pharmacokinetics of oral Beta-P or Dex-P to minimize fetal exposure while achieving the desired treatment responses.

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Section: Discussionmentioning

confidence: 99%

Oral dosing for antenatal corticosteroids in the Rhesus macaque

Schmidt

Kemp

Milad³

et al. 2019

PLoS ONE

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“…The pharmacokinetics (PKs) of ACS have been assessed in pregnant rats and sheep, but not in humans . Furthermore, the available information about the PKs and pharmacodynamics (PDs) of these drugs in humans is dated, incomplete, and based on analytical assays that were not sensitive at the low concentrations that are effective for fetal lung maturation.…”

mentioning

confidence: 99%

“…12,13 The pharmacokinetics (PKs) of ACS have been assessed in pregnant rats and sheep, but not in humans. 8,14,15 Furthermore, the available information about the PKs and pharmacodynamics (PDs) of these drugs in humans is dated, incomplete, and based on analytical assays that were not sensitive at the low concentrations that are effective for fetal lung maturation. As more is now known about fetal maturational responses to antenatal steroids from animal models, 9,16 we report high resolution PK and PD evaluations of Beta and Dex in healthy reproductive age women in India to support the development of novel ACS regimens for use in low and middle-income countries and potentially for worldwide use.…”

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confidence: 99%

Pharmacokinetics and Pharmacodynamics of Intramuscular and Oral Betamethasone and Dexamethasone in Reproductive Age Women in India

Jobe

Milad²,

Peppard

et al. 2019

Clinical Translational Sci

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High‐dose betamethasone and dexamethasone are standard of care treatments for women at risk of preterm delivery to improve neonatal respiratory and mortality outcomes. The dose in current use has never been evaluated to minimize exposures while assuring efficacy. We report the pharmacokinetics and pharmacodynamics (PDs) of oral and intramuscular treatments with single 6 mg doses of dexamethasone phosphate, betamethasone phosphate, or a 1:1 mixture of betamethasone phosphate and betamethasone acetate in reproductive age South Asian women. Intramuscular or oral betamethasone has a terminal half‐life of 11 hours, about twice as long as the 5.5 hours for oral and intramuscular dexamethasone. The 1:1 mixture of betamethasone phosphate and betamethasone acetate shows an immediate release of betamethasone followed by a slow release where plasma betamethasone can be measured out to 14 days after the single dose administration, likely from a depo formed at the injection site by the acetate. PD responses were: increased glucose, suppressed cortisol, increased neutrophils, and suppressed basophils, CD3CD4 and CD3CD8 lymphocytes. PD responses were comparable for betamethasone and dexamethasone, but with longer times to return to baseline for betamethasone. The 1:1 mixture of betamethasone phosphate and betamethasone acetate caused much longer adrenal suppression because of the slow release. These results will guide the development of better treatment strategies to minimize fetal and maternal drug exposures for women at risk of preterm delivery.

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“…Following satisfactory calibration, population prediction was achieved by performing sensitivity analysis and Monte Carlo simulations. The population nonpregnancy model was extended to pregnancy by incorporating physiological changes in pregnancy 4 , 44 , 45 . The pregnancy model was simulated to predict pharmacokinetic data for the second and third trimester of pregnancy using a verification dataset 30 .…”

Section: Discussionmentioning

confidence: 99%

“…Pregnancy-related changes were incorporated as gestational-dependent polynomial equations adapted from several publications 4 , 44 , 45 . The equations used in our model are provided in Supplementary Table 4 .…”

Section: Methodsmentioning

confidence: 99%

Application of physiologically based pharmacokinetic modeling for sertraline dosing recommendations in pregnancy

George¹,

Lumen²,

Nguyen³

et al. 2020

npj Syst Biol Appl

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Pregnancy is a period of significant change that impacts physiological and metabolic status leading to alterations in the disposition of drugs. Uncertainty in drug dosing in pregnancy can lead to suboptimal therapy, which can contribute to disease exacerbation. A few studies show there are increased dosing requirements for antidepressants in late pregnancy; however, the quantitative data to guide dose adjustments are sparse. We aimed to develop a physiologically based pharmacokinetic (PBPK) model that allows gestational-age dependent prediction of sertraline dosing in pregnancy. A minimal physiological model with defined gut, liver, plasma, and lumped placental-fetal compartments was constructed using the ordinary differential equation solver package, ‘mrgsolve’, in R. We extracted data from the literature to parameterize the model, including sertraline physicochemical properties, in vitro metabolism studies, disposition in nonpregnant women, and physiological changes during pregnancy. The model predicted the pharmacokinetic parameters from a clinical study with eight subjects for the second trimester and six subjects for the third trimester. Based on the model, gestational-dependent changes in physiology and metabolism account for increased clearance of sertraline (up to 143% at 40 weeks gestational age), potentially leading to under-dosing of pregnant women when nonpregnancy doses are used. The PBPK model was converted to a prototype web-based interactive dosing tool to demonstrate how the output of a PBPK model may translate into optimal sertraline dosing in pregnancy. Quantitative prediction of drug exposure using PBPK modeling in pregnancy will support clinically appropriate dosing and increase the therapeutic benefit for pregnant women.

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Evaluation of Maternal Drug Exposure Following the Administration of Antenatal Corticosteroids During Late Pregnancy Using Physiologically‐Based Pharmacokinetic Modeling

Cited by 30 publications

References 38 publications

Oral dosing for antenatal corticosteroids in the Rhesus macaque

Oral dosing for antenatal corticosteroids in the Rhesus macaque

Pharmacokinetics and Pharmacodynamics of Intramuscular and Oral Betamethasone and Dexamethasone in Reproductive Age Women in India

Application of physiologically based pharmacokinetic modeling for sertraline dosing recommendations in pregnancy

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