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Paracetamol Concentrations and Time-Course of Ductus Arteriosus Diameter in Extremely Preterm Neonates: A Population
Faheemah Padavia1,2, Jean-Marc Treluyer3,4,5,6, Gilles Cambonie7,8
1Université Paris Cité, Inserm, Pharmacologie et évaluation des thérapeutiques chez l'enfant et la femme enceinte, 75006, Paris, France. faheemah.padavia@aphp.fr.
Insights
Intravenous paracetamol effectively closes the patent ductus arteriosus in extremely preterm infants. A higher initial dose accelerates ductus closure, offering a potentially safer alternative to NSAIDs.
Area of Science:
- Neonatal pharmacology
- Pediatric cardiology
- Pharmacometrics
Background:
- Patent ductus arteriosus (PDA) is a frequent complication in extremely preterm infants.
- Current treatments like indomethacin and ibuprofen do not reduce mortality or morbidity.
- Paracetamol presents a potentially safer prophylactic treatment option.
Purpose of the Study:
- To develop a pharmacokinetic-pharmacodynamic (PKPD) model for intravenous paracetamol's effect on ductus arteriosus diameter.
- To evaluate the efficacy of different paracetamol dosing regimens in extremely preterm neonates.
Main Methods:
- A PKPD model was constructed using an Imax model with an effect compartment.
- Extremely preterm neonates (23-26 weeks gestation) received prophylactic IV paracetamol for 5 days.
- Duaductus arteriosus diameter was monitored daily via echocardiography; PKPD modeling simulated concentrations in 500 virtual patients.
Main Results:
- Two subpopulations with distinct maximal inhibition (Imax) values were identified (99% and 42%).
- Fraction of inspired oxygen and ventilation influenced the transfer rate constant (ke0).
- The higher paracetamol dose (25 mg/kg loading, 10 mg/kg maintenance) achieved 95% maximal inhibition faster, with over 90% of patients reaching the threshold by day one.
Conclusions:
- A PKPD model effectively describes paracetamol's effect on ductus arteriosus diameter in extremely preterm neonates.
- IV paracetamol, particularly a 25 mg/kg loading dose followed by 10 mg/kg every 6h, accelerates ductus closure.
- Increasing the dose beyond this regimen offers limited additional benefit.
Background:
Patent ductus arteriosus is a common complication of extreme prematurity. Prophylactic treatment with indomethacin or ibuprofen has shown efficacy on ductus closure but without reducing mortality and morbidity. Prophylactic treatment by paracetamol could be a safer alternative.
Objective:
The aim was to build a pharmacokinetic-pharmacodynamic (PKPD) model describing the effect of paracetamol on the time-course of the ductus arteriosus diameter.
Methods:
Extremely preterm neonates of 23-26 weeks of gestational age were recruited within 12 h after birth and were treated with prophylactic intravenous paracetamol for 5 days (two dose levels: 20 mg/kg followed by 7.5 mg/kg or 25 mg/kg followed by 10 mg/kg every 6 h). The diameter of ductus arteriosus was determined by echocardiography performed daily until day 7. The PKPD model was built using an Imax model with effect compartment and exponential disease progression model. Concentrations of paracetamol in the effect compartment were simulated with different doses over time for 500 virtual patients.
Results:
A total of 29 extremely preterm neonates with median birth weight of 800 g (IQR: 670-860) were included in the study. Between-subject variability was estimated on transfer rate constant between the central compartment and the effect compartment (ke0) and maximum drug inhibition (Imax) parameters. Two subpopulations with different Imax values were identified: 99% for a first subpopulation of 10 patients and 42% for the second subpopulation of 19 patients. A negative effect of maximum fraction of inspired oxygen (FiO2) used during transfer to intensive care unit and a positive effect of intubation and ventilation during treatment were significant on ke0. Simulations showed that both dose levels generally enabled patients to reach the concentration needed to achieve 95% of maximal inhibition by the end of treatment. However, the second dose level enabled more than 90% of patients to reach this inhibition threshold as early as day one.
Conclusion:
The relationship between paracetamol and the time-course of ductus arteriosus diameter has been described in extremely preterm neonates. Intravenous paracetamol treatment with a loading dose of 25 mg/kg within 12 h after birth followed by 10 mg/kg every 6 h appears to be effective to accelerate time to ductus closure with limited benefit of a further dose increase.
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