Oral dosing for antenatal corticosteroids in the Rhesus macaque

English version

Autoři: Augusto F. Schmidt ^aff001; Matthew W. Kemp ^aff002; Mark Milad ^aff003; Lisa A. Miller ^aff004; James P. Bridges ^aff001; Michael W. Clarke ^aff005; Paranthaman S. Kannan ^aff001; Alan H. Jobe ^aff001
Působiště autorů: Department of Neonatology and Pulmonary Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati, Cincinnati, Ohio, United States of America ^aff001; University of Western Australia, Perth, Australia ^aff002; Milad Pharmaceutical consulting LLC, Plymouth, Michigan, United States of America ^aff003; California National Primate Research Center, University of California, Davis, Davis, California, United States of America ^aff004; Metabolomics Australia, Centre for Microscopy, Characterization and Analysis, The University of Western Australia, Perth, WA, Australia ^aff005
Vyšlo v časopise: PLoS ONE 14(9)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0222817

Souhrn

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.

Klíčová slova:

Biology and life sciences – Organisms – Eukaryota – Animals – Vertebrates – Amniotes – Mammals – Primates – Monkeys – Old World monkeys – Macaque – Ruminants – Sheep – Anatomy – Body fluids – Blood – Blood plasma – Brain – Hippocampus – Physiology – Medicine and health sciences – Pharmacology – Pharmacokinetics – Pharmaceutics – Drug therapy

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Oral dosing for antenatal corticosteroids in the Rhesus macaque

Souhrn

Klíčová slova:

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