{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,13]],"date-time":"2025-12-13T07:33:01Z","timestamp":1765611181893,"version":"3.48.0"},"reference-count":34,"publisher":"BMJ","issue":"6","license":[{"start":{"date-parts":[[2025,6,8]],"date-time":"2025-06-08T00:00:00Z","timestamp":1749340800000},"content-version":"unspecified","delay-in-days":7,"URL":"https:\/\/creativecommons.org\/licenses\/by\/3.0\/igo\/"}],"funder":[{"DOI":"10.13039\/100000865","name":"Bill and Melinda Gates Foundation","doi-asserted-by":"publisher","award":["INV-005390"],"award-info":[{"award-number":["INV-005390"]}],"id":[{"id":"10.13039\/100000865","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["BMJ Open"],"accepted":{"date-parts":[[2025,4,25]]},"published-print":{"date-parts":[[2025,6]]},"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Antenatal corticosteroid (ACS) regimens have remained unchanged since the initial trials in 1972, with the optimal regimen still undetermined. The WHO ACTION (Antenatal CorticosTeroids for Improving Outcomes in preterm Newborns)-III trial is a three-arm individually randomised double-blind trial evaluating the efficacy and safety of two different ACS dosing regimens (currently used and lower-dose ACS regimens vs placebo) in women with a high probability of having a late preterm birth. This study protocol nested within this trial aims to evaluate the pharmacokinetics (PK) and pharmacodynamics (PD) effects of two different ACS dosing regimens in pregnant women in the late preterm period (34\u201336 weeks) to help inform an optimal dosing regimen.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods and analysis<\/jats:title>\n                    <jats:p>The study will be conducted in two of the five countries participating in the WHO ACTION-III trial\u2014India (Delhi, Belagavi) and Nigeria (Ibadan and Ile-Ife). We will use a population PK approach using sparse sampling to study the PK effects of the two ACS regimens, that is, 6\u2009mg dexamethasone phosphate (DEXp) or 2\u2009mg betamethasone phosphate (BETp), administered intramuscularly every 12 hours for a maximum of four doses or till birth, whichever is earlier, compared with placebo. We will also ascertain the fetal\u2013maternal ratio of DEXp and BETp at birth.<\/jats:p>\n                    <jats:p>Maternal venous blood samples will be collected at 0, 1\u20134\u2009hours, 8\u201312\u2009hours after the first dose, and at 24\u201336\u2009hours, 48\u201360\u2009hours, 72\u201396\u2009hours after the last dose, and immediately after birth, along with cord blood. Concentrations of DEXp and BETp will be measured at set time points using a validated liquid chromatography mass spectroscopy assay. PD parameters measured will include total and differential white blood cell count (by automated analysers using electrical impedance), plasma glucose (hexokinase method) and serum cortisol (using a validated electrochemiluminescence immunoassay), at predefined time points. PK models will be developed for each drug using non-linear mixed effects methods. Optimal dosing will be investigated using Monte Carlo simulations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Ethics and dissemination<\/jats:title>\n                    <jats:p>The study has been approved by the WHO Ethics Review Committee and the site-specific ethics committees of the participating leading institutions. Written informed consent will be obtained from all participants. The study results will be published in a peer-reviewed journal and presented at scientific conferences.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Trial registration number<\/jats:title>\n                    <jats:p>\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"isrctn\" xlink:href=\"ISRCTN11434567\">ISRCTN11434567<\/jats:ext-link>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1136\/bmjopen-2024-096523","type":"journal-article","created":{"date-parts":[[2025,6,8]],"date-time":"2025-06-08T15:45:23Z","timestamp":1749397523000},"page":"e096523","update-policy":"https:\/\/doi.org\/10.1136\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":0,"title":["Population pharmacokinetics and pharmacodynamics of two dosing regimens of antenatal corticosteroids: protocol for a prospective nested study in a randomised controlled trial"],"prefix":"10.1136","volume":"15","clinical-trial-number":[{"clinical-trial-number":"isrctn11434567","registry":"10.18810\/isrctn"}],"author":[{"name":"The WHO ACTION-III PK PD Collaborators","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2025,6,8]]},"reference":[{"key":"2025121223270059000_15.6.e096523.1","article-title":"Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth","volume":"12","author":"McGoldrick","year":"2020","journal-title":"Cochrane Database Syst Rev"},{"key":"2025121223270059000_15.6.e096523.2","unstructured":"World Health Organization . WHO recommendations on antenatal corticosteroids for improving preterm birth outcomes, Geneva, 2022. Available: https:\/\/iris.who.int\/bitstream\/handle\/10665\/363131\/9789240057296-eng.pdf?sequence=1"},{"key":"2025121223270059000_15.6.e096523.3","unstructured":"Annex W . Evidence-to-decision framework. In: WHO recommendation on antenatal corticosteroids for improving preterm birth outcomes. Geneva: World Health Organization, 2022. 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