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. 2025 Nov;64(11):1681-1691.
doi: 10.1007/s40262-025-01567-4. Epub 2025 Sep 1.

Paracetamol Concentrations and Time-Course of Ductus Arteriosus Diameter in Extremely Preterm Neonates: A Population Pharmacokinetic-Pharmacodynamic Analysis

Faheemah Padavia  1   2 , Jean-Marc Treluyer  3   4   5   6 , Gilles Cambonie  7   8 , Cyril Flamant  9 , Aline Rideau  10 , Manon Tauzin  11 , Juliana Patkai  12 , Géraldine Gascoin  13 , Mirka Lumia  14 , Outi Aikio  15 , Frantz Foissac  3   4   5 , Saïk Urien  3   4   5 , Sihem Benaboud  3   6 , Gabrielle Lui  3   6 , Léo Froelicher Bournaud  3   6 , Yi Zheng  6 , Ruth Kemper  16 , Marine Tortigue  17   18   19 , Alban-Elouen Baruteau  17   18   19   20 , Jaana Kallio  14 , Mikko Hallman  15 , Alpha Diallo  21   22 , Léa Levoyer  21   22 , Jean-Christophe Roze  19   20 , Naïm Bouazza  3   4   5
Affiliations

Paracetamol Concentrations and Time-Course of Ductus Arteriosus Diameter in Extremely Preterm Neonates: A Population Pharmacokinetic-Pharmacodynamic Analysis

Faheemah Padavia et al. Clin Pharmacokinet. 2025 Nov.

Abstract

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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Conflict of interest statement

Declarations. Funding: Institut national de la santé et de la recherche médicale (Inserm) is the sponsor of the TREOCAPA trial. The project leading to this application has received funding through the Connect4Children consortium from the Innovative Medicines Initiative 2 Joint Undertaking under Grant Agreement n°777389. This joint undertaking receives support from the European Union’s Horizon 2020 research and innovation programme and EFPIA. Role of the funder/sponsor: The funding organisation had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. Conflict Of Interest: Faheemah PADAVIA, Jean-Marc TRELUYER, Gilles CAMBONIE, Cyril FLAMANT, Aline RIDEAU, Manon TAUZIN, Juliana PATKAI, Géraldine GASCOIN, Mirka LUMIA, Outi AIKIO, Frantz FOISSAC, Saïk URIEN, Sihem BENABOUD, Gabrielle LUI, Léo FROELICHER BOURNAUD, Yi ZHENG, Ruth KEMPER, Marine TORTIGUE, Alban-Elouen BARUTEAU, Jaana KALLIO, Mikko HALLMAN, Alpha DIALLO, Léa LEVOYER, Jean-Christophe ROZE and Naïm BOUAZZA declare that they have no potential conflicts of interest that might be relevant to the contents of this manuscript. Ethics approval: The trial was approved by the ethics committee of the Centre Hospitalier La Chartreuse under the approval number SI 20.03.09.40128 for France and by the regional medical research ethics committee of North Ostrobothnia under the approval number 68/06.00.00/20 19 for Finland. Consent to participate: Written informed consent was obtained from both parents. Consent for publication: Not applicable. Data availability statement: The data that support the findings of this study are available from Institut national de la santé et de la recherche médicale (Inserm) but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available. Data are, however, available from the authors upon reasonable request and with the permission of Inserm. Author Contributions: Concept and design: NB, MH, JMT, JCR. Acquisition of data: GC, CF, AR, MT, JP, GG, ML, OA, YZ, MT, AEB. Analysis and interpretation of data: FP, NB, FF, SU, JCR. Drafting of the manuscript: FP, NB, FF, SU, GL, LFB, JCR. Critical revision of the manuscript for important intellectual content: All authors.

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