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Updated: Jun 16, 2025
Comprehensive Evaluation of the Effectiveness and Safety of Placenta-Targeted Drug Delivery Using Three Complementary Methods
Published on: September 10, 2018
Population pharmacokinetics and pharmacodynamics of two dosing regimens of antenatal corticosteroids: protocol for a
Insights
This study investigates the pharmacokinetics and pharmacodynamics of antenatal corticosteroid (ACS) regimens in late preterm birth to optimize treatment. Findings will inform safer and more effective ACS dosing for improved neonatal outcomes.
Area of Science:
- Pharmacology
- Neonatal Medicine
- Clinical Trials
Background:
- Antenatal corticosteroid (ACS) regimens have not been updated since 1972, leaving optimal dosing undetermined.
- The WHO ACTION-III trial evaluates ACS efficacy and safety in late preterm birth (34-36 weeks).
- This nested study protocol aims to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of different ACS dosing regimens.
Purpose of the Study:
- To evaluate the PK and PD effects of two different ACS dosing regimens in pregnant women at high risk for late preterm birth.
- To inform the development of an optimal ACS dosing regimen for improved neonatal outcomes.
- To determine the fetal-maternal ratio of dexamethasone phosphate (DEXp) and betamethasone phosphate (BETp) at birth.
Main Methods:
- Population PK analysis with sparse sampling will be employed.
- Maternal blood and cord blood samples will be collected at defined time points for DEXp and BETp concentration measurement using liquid chromatography-mass spectrometry.
- PD parameters including white blood cell count, plasma glucose, and serum cortisol will be measured.
Main Results:
- PK models will be developed using non-linear mixed effects methods.
- Monte Carlo simulations will be used to investigate optimal dosing strategies.
- Fetal-maternal drug ratios will be ascertained.
Conclusions:
- This research will provide crucial PK/PD data to guide optimal antenatal corticosteroid dosing.
- Findings are expected to enhance the safety and efficacy of ACS for preventing complications in late preterm infants.
- The study contributes to evidence-based guidelines for managing preterm birth risks.
Introduction:
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 (34-36 weeks) to help inform an optimal dosing regimen.
Methods And Analysis:
The study will be conducted in two of the five countries participating in the WHO ACTION-III trial-India (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 mg dexamethasone phosphate (DEXp) or 2 mg 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-maternal ratio of DEXp and BETp at birth.Maternal venous blood samples will be collected at 0, 1-4 hours, 8-12 hours after the first dose, and at 24-36 hours, 48-60 hours, 72-96 hours 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.
Ethics And Dissemination:
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.
Trial Registration Number:
ISRCTN11434567.
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