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

Zdroje

1. Roberts D, Brown J, Medley N, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2017;3:CD004454. doi: 10.1002/14651858.CD004454.pub3 28321847.

2. Vogel JP, Oladapo OT, Pileggi-Castro C, Adejuyigbe EA, Althabe F, Ariff S, et al. Antenatal corticosteroids for women at risk of imminent preterm birth in low-resource countries: the case for equipoise and the need for efficacy trials. BMJ Glob Health. 2017;2(3):e000398. doi: 10.1136/bmjgh-2017-000398 29082019; PubMed Central PMCID: PMC5656119.

3. Glasziou P, Straus S, Brownlee S, Trevena L, Dans L, Guyatt G, et al. Evidence for underuse of effective medical services around the world. Lancet. 2017;390(10090):169–77. Epub 2017/01/13. doi: 10.1016/S0140-6736(16)30946-1 28077232.

4. WHO Recommendations on Interventions to Improve Preterm Birth Outcomes. Geneva: World Health Organization; 2015. 3, Evidence and recommendations. Available from: https://www.ncbi.nlm.nih.gov/books/NBK321168/

5. Griffin JB, Jobe AH, Rouse D, McClure EM, Goldenberg RL, Kamath-Rayne BD. Evaluating WHO-Recommended Interventions for Preterm Birth: A Mathematical Model of the Potential Reduction of Preterm Mortality in Sub-Saharan Africa. Glob Health Sci Pract. 2019;7(2):215–27. Epub 2019/06/30. doi: 10.9745/GHSP-D-18-00402 31249020; PubMed Central PMCID: PMC6641817.

6. Gyamfi-Bannerman C, Thom EA, Blackwell SC, Tita AT, Reddy UM, Saade GR, et al. Antenatal Betamethasone for Women at Risk for Late Preterm Delivery. N Engl J Med. 2016;374(14):1311–20. Epub 2016/02/05. doi: 10.1056/NEJMoa1516783 26842679; PubMed Central PMCID: PMC4823164.

7. Althabe F, Belizan JM, McClure EM, Hemingway-Foday J, Berrueta M, Mazzoni A, et al. A population-based, multifaceted strategy to implement antenatal corticosteroid treatment versus standard care for the reduction of neonatal mortality due to preterm birth in low-income and middle-income countries: the ACT cluster-randomised trial. Lancet. 2015;385(9968):629–39. doi: 10.1016/S0140-6736(14)61651-2 25458726; PubMed Central PMCID: PMC4420619.

8. Jobe AH, Goldenberg RL. Antenatal corticosteroids: an assessment of anticipated benefits and potential risks. Am J Obstet Gynecol. 2018;219(1):62–74. Epub 2018/04/10. doi: 10.1016/j.ajog.2018.04.007 29630886.

9. Kemp MW, Jobe AH, Usuda H, Nathanielsz PW, Li C, Kuo A, et al. Efficacy and Safety of Antenatal Steroids. Am J Physiol Regul Integr Comp Physiol. 2018. Epub 2018/04/12. doi: 10.1152/ajpregu.00193.2017 29641233.

10. Brownfoot FC, Gagliardi DI, Bain E, Middleton P, Crowther CA. Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2013;(8):CD006764. doi: 10.1002/14651858.CD006764.pub3 23990333.

11. Schmidt AF, Kemp MW, Rittenschober-Bohm J, Kannan PS, Usuda H, Saito M, et al. Low-dose betamethasone-acetate for fetal lung maturation in preterm sheep. Am J Obstet Gynecol. 2018;218(1):132 e1– e9. Epub 2017/11/16. doi: 10.1016/j.ajog.2017.11.560 29138038; PubMed Central PMCID: PMC5759749.

12. Schmidt AF, Kannan PS, Bridges JP, Filuta A, Lipps D, Kemp M, et al. Dosing and formulation of antenatal corticosteroids for fetal lung maturation and gene expression in rhesus macaques. Sci Rep. 2019;9(1):9039. doi: 10.1038/s41598-019-45171-6 31227752; PubMed Central PMCID: PMC6588577

13. Kemp MW, Saito M, Usuda H, Watanabe S, Sato S, Hanita T, et al. The efficacy of antenatal steroid therapy is dependent on the duration of low-concentration fetal exposure: evidence from a sheep model of pregnancy. Am J Obstet Gynecol. 2018;219(3):301 e1– e16. Epub 2018/05/15. doi: 10.1016/j.ajog.2018.05.007 29758177.

14. Waljee AK, Rogers MA, Lin P, Singal AG, Stein JD, Marks RM, et al. Short term use of oral corticosteroids and related harms among adults in the United States: population based cohort study. BMJ. 2017;357:j1415. doi: 10.1136/bmj.j1415 28404617.

15. Schmidt AF, Jobe AH, Kannan PS, Bridges JP, Newnham JP, Saito M, et al. Oral antenatal corticosteroids evaluated in fetal sheep. Pediatr Res. 2019. Epub 2019/08/01. doi: 10.1038/s41390-019-0519-0 31365919.

16. Senthamaraikannan P, Presicce P, Rueda CM, Maneenil G, Schmidt AF, Miller LA, et al. Intra-amniotic Ureaplasma parvum-Induced Maternal and Fetal Inflammation and Immune Responses in Rhesus Macaques. J Infect Dis. 2016;214(10):1597–604. Epub 2016/10/30. doi: 10.1093/infdis/jiw408 27601620.

17. Kemp MW, Saito M, Usuda H, Molloy TJ, Miura Y, Sato S, et al. Maternofetal pharmacokinetics and fetal lung responses in chronically catheterized sheep receiving constant, low-dose infusions of betamethasone phosphate. Am J Obstet Gynecol. 2016;215(6):775 e1– e12. doi: 10.1016/j.ajog.2016.08.017 27555319.

18. Jobe AH, Newnham JP, Willet KE, Moss TJ, Gore Ervin M, Padbury JF, et al. Endotoxin-induced lung maturation in preterm lambs is not mediated by cortisol. Am J Respir Crit Care Med. 2000;162(5):1656–61. Epub 2000/11/09. doi: 10.1164/ajrccm.162.5.2003044 11069792.

19. Dobin A, Gingeras TR. Mapping RNA-seq Reads with STAR. Curr Protoc Bioinformatics. 2015;51:11 4 1–9. Epub 2015/09/04. doi: 10.1002/0471250953.bi1114s51 26334920; PubMed Central PMCID: PMC4631051.

20. Anders S, Huber W. Differential expression analysis for sequence count data. Genome Biol. 2010;11(10):R106. doi: 10.1186/gb-2010-11-10-r106 20979621; PubMed Central PMCID: PMC3218662.

21. Reimand J, Arak T, Adler P, Kolberg L, Reisberg S, Peterson H, et al. g:Profiler-a web server for functional interpretation of gene lists (2016 update). Nucleic Acids Res. 2016;44(W1):W83–9. doi: 10.1093/nar/gkw199 27098042; PubMed Central PMCID: PMC4987867.

22. Kemp MW, Saito M, Usuda H, Watanabe S, Sato S, Hanita T, et al. The efficacy of antenatal steroid therapy is dependent on the duration of low-concentration fetal exposure: Evidence from a sheep model of pregnancy. Am J Obstet Gynecol. 2018. Epub 2018/05/15. doi: 10.1016/j.ajog.2018.05.007 29758177.

23. Egerman RS, Mercer BM, Doss JL, Sibai BM. A randomized, controlled trial of oral and intramuscular dexamethasone in the prevention of neonatal respiratory distress syndrome. Am J Obstet Gynecol. 1998;179(5):1120–3. Epub 1998/11/20. doi: 10.1016/s0002-9378(98)70116-4 9822485.

24. Elliott CL, Read GF, Wallace EM. The pharmacokinetics of oral and intramuscular administration of dexamethasone in late pregnancy. Acta Obstet Gynecol Scand. 1996;75(3):213–6. Epub 1996/03/01. doi: 10.3109/00016349609047089 8607331.

25. Liggins GC, Howie RN. A controlled trial of antepartum glucocorticoid treatment for prevention of the respiratory distress syndrome in premature infants. Pediatrics. 1972;50(4):515–25. 4561295.

26. Jobe AH, Newnham J, Willet K, Sly P, Ikegami M. Fetal versus maternal and gestational age effects of repetitive antenatal glucocorticoids. Pediatrics. 1998;102(5):1116–25. doi: 10.1542/peds.102.5.1116 9794943.

27. Egerman RS, Pierce WFt, Andersen RN, Umstot ES, Carr TL, Sibai BM. A comparison of the bioavailability of oral and intramuscular dexamethasone in women in late pregnancy. Obstet Gynecol. 1997;89(2):276–80. doi: 10.1016/S0029-7844(96)00446-2 9015035.

28. Queckenberg C, Wachall B, Erlinghagen V, Di Gion P, Tomalik-Scharte D, Tawab M, et al. Pharmacokinetics, pharmacodynamics, and comparative bioavailability of single, oral 2-mg doses of dexamethasone liquid and tablet formulations: a randomized, controlled, crossover study in healthy adult volunteers. Clin Ther. 2011;33(11):1831–41. Epub 2011/11/04. doi: 10.1016/j.clinthera.2011.10.006 22047811.

29. Santolaya-Forgas J, Duval J, Prespin C, Vengalil S, Kushwaha A, Wilson L, et al. Extracoelomic fluid osmometry and electrolyte composition during early gestation in the baboon. Am J Obstet Gynecol. 1998;179(5):1124–7. doi: 10.1016/s0002-9378(98)70117-6 9822486.

30. Roberts D, Dalziel S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2006;(3):CD004454. doi: 10.1002/14651858.CD004454.pub2 16856047.

31. Tan RC, Ikegami M, Jobe AH, Yao LY, Possmayer F, Ballard PL. Developmental and glucocorticoid regulation of surfactant protein mRNAs in preterm lambs. Am J Physiol. 1999;277(6):L1142–8. Epub 1999/12/22. doi: 10.1152/ajplung.1999.277.6.L1142 10600884.

32. Ballard PL, Ballard RA. Scientific basis and therapeutic regimens for use of antenatal glucocorticoids. Am J Obstet Gynecol. 1995;173(1):254–62. Epub 1995/07/01. doi: 10.1016/0002-9378(95)90210-4 7631700.

33. Ke AB, Milad MA. Evaluation of Maternal Drug Exposure Following the Administration of Antenatal Corticosteroids During Late Pregnancy Using Physiologically-Based Pharmacokinetic Modeling. Clin Pharmacol Ther. 2019;106(1):164–73. Epub 2019/03/30. doi: 10.1002/cpt.1438 30924921.

Oral dosing for antenatal corticosteroids in the Rhesus macaque

Souhrn

Klíčová slova:

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