Oral dosing for antenatal corticosteroids in the Rhesus macaque

Augusto F Schmidt, Matthew W Kemp, Mark Milad, Lisa A Miller, James P Bridges, Michael W Clarke, Paranthaman S Kannan, Alan H Jobe

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish
Article numbere0222817
Number of pages14
JournalPLoS One
Volume14
Issue number9
DOIs
Publication statusPublished - 19 Sep 2019

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dexamethasone 21-phosphate
adrenal cortex hormones
Macaca mulatta
mouth
Adrenal Cortex Hormones
betamethasone
phosphates
Pharmacokinetics
Mothers
dexamethasone
Blood
Macaca
Gene expression
Liver
Lung
Haplorhini
Hippocampus
Acetates
Steroids
Pharmaceutical Preparations

Cite this

Schmidt, A. F., Kemp, M. W., Milad, M., Miller, L. A., Bridges, J. P., Clarke, M. W., ... Jobe, A. H. (2019). Oral dosing for antenatal corticosteroids in the Rhesus macaque. PLoS One, 14(9), [e0222817]. https://doi.org/10.1371/journal.pone.0222817
Schmidt, Augusto F ; Kemp, Matthew W ; Milad, Mark ; Miller, Lisa A ; Bridges, James P ; Clarke, Michael W ; Kannan, Paranthaman S ; Jobe, Alan H. / Oral dosing for antenatal corticosteroids in the Rhesus macaque. In: PLoS One. 2019 ; Vol. 14, No. 9.
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Schmidt, AF, Kemp, MW, Milad, M, Miller, LA, Bridges, JP, Clarke, MW, Kannan, PS & Jobe, AH 2019, 'Oral dosing for antenatal corticosteroids in the Rhesus macaque' PLoS One, vol. 14, no. 9, e0222817. https://doi.org/10.1371/journal.pone.0222817

Oral dosing for antenatal corticosteroids in the Rhesus macaque. / Schmidt, Augusto F; Kemp, Matthew W; Milad, Mark; Miller, Lisa A; Bridges, James P; Clarke, Michael W; Kannan, Paranthaman S; Jobe, Alan H.

In: PLoS One, Vol. 14, No. 9, e0222817, 19.09.2019.

Research output: Contribution to journalArticle

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AU - Schmidt, Augusto F

AU - Kemp, Matthew W

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AU - Kannan, Paranthaman S

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