Oral antenatal corticosteroids evaluated in fetal sheep

Abstract

BackgroundThe use of antenatal corticosteroids (ACS) in low-resource environments is sporadic. Further, drug choice, dose, and route of ACS are not optimized. We report the pharmacokinetics and pharmacodynamics of oral dosing of ACS using a preterm sheep model.MethodsWe measured pharmacokinetics of oral betamethasone-phosphate (Beta-P) and dexamethasone-phosphate (Dex-P) using catheterized pregnant sheep. We compared fetal lung maturation responses of oral Beta-P and Dex-P to the standard treatment with 2 doses of the i.m. mixture of Beta-P and betamethasone-acetate at 2, 5, and 7 days after initiation of ACS.ResultsOral Dex-P had lower bioavailability than Beta-P, giving a lower maximum maternal and fetal concentration. A single oral dose of 0.33 mg/kg of Beta-P was equivalent to the standard clinical treatment assessed at 2 days; 2 doses of 0.16 mg/kg of oral Beta-P were equivalent to the standard clinical treatment at 7 days as assessed by lung mechanics and gas exchange after preterm delivery and ventilation. In contrast, oral Dex-P was ineffective because of its decreased bioavailability.ConclusionUsing a sheep model, we demonstrate the use of pharmacokinetics to develop oral dosing strategies for ACS. Oral dosing is feasible and may facilitate access to ACS in low-resource environments.

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

“…This study resulted from our PK and PD measurements in sheep and monkey preterm birth models indicating that current ACS treatments likely are exposing mother and fetus to high blood levels of the steroids for longer than necessary. 11,13,16 This study in reproductive age nonpregnant Indian Asian women evaluated the PK and PD responses to 6 mg DexP i.m., as it is the most commonly used regimen in low resource environments when given four times, 12 hours apart. 3 To better understand other treatment options, we also evaluated 6 mg BetaP and BetaP plus BetaA, but at the 6 mg dose rather than the clinical dose of 12 mg.…”

“…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 . 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 …”

“…[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. 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.…”

Antenatal corticosteroids: a reappraisal of the drug formulation and dose

“…However, the need for a prolonged fetal exposure was never verified as essential for the clinical response until we tested the Beta Ac component of the two-drug combination used in clinical practice in sheep and monkey models recently. [7][8][9][10][11][12][13][14][15][16] Most of the repeat treatment regimens that are used worldwide have not been tested for safety and efficacy.…”

Optimizing antenatal corticosteroid therapy for improving outcome of premature infants

“…In this issue of the Journal, Schmidt and colleagues report pharmacokinetics and biologic effects of oral ACS therapy for lung maturation in sheep (8). It is astonishing to realize that, as these authors point out, "despite being used for nearly 50 years, the corticosteroid, dose, treatment interval and route of treatment remain largely unexplored (8). "…”