The efficacy of antenatal steroid therapy is dependent on the duration of low-concentration fetal exposure: evidence from a sheep model of pregnancy

Kemp, Matthew W.; Saito, Masatoshi; Usuda, Haruo; Watanabe, Shimpei; Sato, Shinichi; Hanita, Takushi; Kumagai, Yusaku; Molloy, Timothy J.; Clarke, Michael; Eddershaw, Peter; Musk, Gabrielle C.; Schmidt, Augusto F.; Ireland, Demelza J.; Furfaro, Lucy; Payne, Matthew S.; Newnham, John P.; Jobe, Alan H.

doi:10.1016/j.ajog.2018.05.007

Cited by 43 publications

(51 citation statements)

References 29 publications

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“…They also showed that achievement and maintenance of low fetal betamethasone levels (i.e., in the range 1-4 ng/mL) over a sufficient duration could provide a similar ACT efficacy. 35,36 The authors also point out that the effectiveness could be of limited duration as it has been shown in very premature human lung explants that maturational signals from ACT are reversible if steroids are removed. 36,37 This was also reported in a clinical study published by Norman et al, 38 showing that for all evaluated outcomes, the risk reduction associated with ACT was transient.…”

Section: Discussionmentioning

confidence: 99%

Maternal Betamethasone for Prevention of Respiratory Distress Syndrome in Neonates: Population Pharmacokinetic and Pharmacodynamic Approach

Foissac

Zheng

Hirt

et al. 2020

Clin Pharma and Therapeutics

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Section: Discussionmentioning

confidence: 99%

Maternal Betamethasone for Prevention of Respiratory Distress Syndrome in Neonates: Population Pharmacokinetic and Pharmacodynamic Approach

Foissac

Zheng

Hirt

et al. 2020

Clin Pharma and Therapeutics

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“…This is primarily because the exposure–response relationships have not been established for ACS despite the long history of use. The target steroid concentration in the human fetus is unknown, yet, based on exposure–response studies in sheep models, a low steroid concentration maintained for 36–48 hours will maximize efficacy while minimize exposure to steroids . A clinical PK/pharmacodynamic study that directly compares dexamethasone and betamethasone to establish an exposure–response relationship for safety in nonpregnant adult women, as well as an estimate of efficacy exposure from sheep models, are currently being used to define a therapeutic window for ACS.…”

Section: Discussionmentioning

confidence: 99%

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

Milad²

2019

Clin Pharma and Therapeutics

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Betamethasone and dexamethasone are the most widely studied antenatal corticosteroids (ACS) administered to pregnant women, just prior to the birth of a preterm neonate, to accelerate fetal lung maturation. Although betamethasone, predominantly used in developed countries, has been shown to be an effective and safe intervention for reducing neonatal mortality, the choice of ACS and optimal dosing in low and middle income countries (LMICs) remains unclear. This is primarily because the exposure-response relationships have not been established for ACS despite the long history of use. As the first step toward the optimal use of ACS in LMICs, we developed physiologically-based pharmacokinetic (PBPK) models to describe the kinetics of ACS following i.v., p.o., or i.m. dosing. In vitro data describing the cytochrome P450 3A4 enzyme contribution were incorporated and this was refined using clinical data. The models can be applied prospectively to predict kinetics of ACS in pregnant women receiving various dosing regimens.Preterm birth is a major cause of death and morbidity in newborns worldwide and the majority of preterm deliveries and deaths occur in sub-Saharan African and South Asian countries. 1 Respiratory morbidity, including respiratory distress syndrome (RDS), is a serious complication of preterm birth and the primary cause of early neonatal mortality and disability. The administration of antenatal corticosteroids (ACS) to a pregnant woman (who is at risk of imminent preterm birth) is recommended to promote fetal

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“…or orally to the mother are rapidly dephosphorylated to yield high maternal and fetal concentrations that may not be necessary for the fetal lung maturation and, thus, may only contribute to fetal toxicity. [10][11][12] All recommended ACS treatments are given maternal i.m., although oral preparations of these steroids are widely available and were recently shown to be comparably effective in preterm sheep and primate models. 12,13 The pharmacokinetics (PKs) of ACS have been assessed in pregnant rats and sheep, but not in humans.…”

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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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The efficacy of antenatal steroid therapy is dependent on the duration of low-concentration fetal exposure: evidence from a sheep model of pregnancy

Cited by 43 publications

References 29 publications

Maternal Betamethasone for Prevention of Respiratory Distress Syndrome in Neonates: Population Pharmacokinetic and Pharmacodynamic Approach

Maternal Betamethasone for Prevention of Respiratory Distress Syndrome in Neonates: Population Pharmacokinetic and Pharmacodynamic Approach

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

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

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