Faheemah Padavia1,2, Jean-Marc Tréluyer1,2,3,4, Gilles Cambonie5,6, Cyril Flamant7, Aline Rideau8, Manon Tauzin9, Juliana Patkai10, Géraldine Gascoin11, Mirka Lumia12, Outi Aikio13, Frantz Foissac1,2,3, Saïk Urien1,2,3, Sihem Benaboud1,4, Gabrielle Lui1,4, Léo Froelicher Bournaud1,4, Yi Zheng4, Ruth Kemper14, Marine Tortigue15,16,17, Alban-Elouen Baruteau15,16,17,18, Jaana Kallio12, Mikko Hallman13, Alpha Diallo19,20, Léa Levoyer19,20, Jean-Christophe Rozé17,18, Naïm Bouazza1,2,3
1Université Paris Cité, Inserm, Pharmacologie et évaluation des thérapeutiques chez l’enfant et la femme enceinte, 2Unité de Recherche Clinique Necker/Cochin, AP-HP, Hôpital Tarnier, 3CIC-1419 Inserm, Cochin-Necker, 4Service de Pharmacologie Clinique, Hôpital Cochin, AP-HP, Groupe Hospitalier Paris Centre, 5Department of Neonatal Medicine and Pediatric Intensive Care, Arnaud de Villeneuve Hospital, Montpellier University Hospital, 6Pathogenesis and Control of Chronic Infection, Inserm, UMR1058, University of Montpellier, 7Department of Neonatalogy, CHU Nantes, 8Department of Pediatrics, Robert Debré Hospital, APHP, 9Neonatal Intensive Care Unit, Centre Hospitalier Intercommunal de Créteil, 10Neonatalogy Department, Port-Royal Hospital, 11Department of Neonatalogy, Angers University Hospital, 12Department of Children and Adolescents, New Children’s Hospital, Pediatric research Center, Helsinki University Hospital and University of Helsinki, 13Department of Pediatrics and Adolescent Medicine, Oulu University Hospital, and Research Unit of Clinical Medicine and MRC Oulu, University of Oulu, 14European Foundation for the Care of Newborn Infants, 15Nantes Université, CHU Nantes, CNRS, Inserm, l’institut du thorax, 16Department of Pediatric Cardiology and Pediatric Cardiac Surgery, FHU PRECICARE, Nantes Université, CHU Nantes, 17Nantes Université, CHU Nantes, Inserm, CIC FEA 1413, 18Nantes Université, INRAE, UMR 1280, PhAN, 19Clinical Trial Safety and Public Health, ANRS Emerging Infectious Diseases, 20Clinical Research Safety Department, Inserm
Introduction: Patent ductus arteriosus is a common complication of extreme prematurity [1]. Prophylactic treatment with indomethacin or ibuprofen has shown efficacy on ductus closure but without reducing of mortality and morbidity because of the numerous adverse effects [2]. Early prophylactic treatment by paracetamol could be a safer alternative for hemodynamically significant PDA [3]. Objectives: The aim was to build a pharmacokinetic-pharmacodynamic (PKPD) model describing the effect of paracetamol on the time course of the ductus arteriosus diameter. Factors associated with between-subject variability (BSV) were studied and simulations were realised to assess the minimum effective dose. Methods: Extreme preterm neonates of 23-26 weeks of gestational age were included within 12 hours after birth and were treated with prophylactic intravenous paracetamol for five days. This study was part of a dose escalation trial with four predefined dose levels [4]. The escalation stopped at the second dose level. Twenty patients received the first dose level (20 mg/kg followed by 7.5 mg/kg/6h) and nine patients received the second dose level (25 mg/kg followed by 10 mg/kg/6h). The diameter of ductus arteriosus was determined by echocardiography performed daily until day 7. The pharmacokinetic (PK) of paracetamol was previously described by a two-compartment model with BSV on clearance and peripheral volume of distribution. Significant positive effects of bodyweight on clearance and birth length on volume of peripheral compartment were also included in the model [5]. The PKPD model was developed by setting all the PK parameters to the previously build model. An Imax model with an effect compartment and an exponential disease progression was performed. Data were analysed using the nonlinear mixed effect modelling software program Monolix (version 2021R2). Paracetamol concentrations in the effect compartment were simulated with different doses over time for 500 virtual patients, accounting for the significant covariates. The percentage of patients with a concentration in the effect compartment above IC95 (concentration needed to achieve 95% of the maximal drug inhibition) was calculated after the first day and at the end of treatment for both dose levels. Results: A total of 29 extreme preterm neonates with median bodyweight of 800 g (IQR: 670 – 860) were included in the study. BSV was estimated on transfer rate constant between the central compartment and the effect compartment (ke0) and maximum drug inhibition (Imax) parameters. The IC50 (concentration needed to achieve 50% of the maximal drug inhibition) and the IC95 were estimated at 9.0 and 19.3 µmol/L respectively. 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 neonatal intensive care unit (NICU) and a positive effect of intubation 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 diameter has been described in extreme preterm neonates. The BSV on ke0 was partially explained by two significant covariates: the maximum FiO2 used during transfer to the NICU, recorded at inclusion, and intubation during treatment as a time-dependent covariate. In our model, a higher FiO2 was associated with a lower ke0, indicating a slower transfer rate of the drug into the effect compartment that could be due to severe respiratory distress and impaired oxygenation. Conversely, intubated patients exhibited a higher ke0, meaning that the drug transfer into the effect compartment was accelerated. This could indicate that intubation and ventilation improves drug distribution mediated by an increase in cardiac output or enhanced systemic circulation. The simulations showed that intravenous paracetamol treatment with a loading dose of 25 mg/kg within 12 hours after birth followed by 10 mg/kg every 6 hours appears to be effective to accelerate time to ductus closure with limited benefit of a further dose increase. References: [1] Dice JE et al. J Pediatr Pharmacol Ther. (2007) 12, 138–46. [2] Sivanandan S et al. Pediatr Drugs. (2016) 18, 123–38. [3] Ohlsson A et al. Cochrane Database Syst Rev. (2018) 4, CD010061. [4] Bouazza N et al. Pediatr Drugs. (2024) 26, 83–93. [5] Padavia F et al. Clin Pharmacokinet. (2024) 63, 1689–700.
[1] Dice JE et al. J Pediatr Pharmacol Ther. (2007) 12, 138–46. [2] Sivanandan S et al. Pediatr Drugs. (2016) 18, 123–38. [3] Ohlsson A et al. Cochrane Database Syst Rev. (2018) 4, CD010061. [4] Bouazza N et al. Pediatr Drugs. (2024) 26, 83–93. [5] Padavia F et al. Clin Pharmacokinet. (2024) 63, 1689–700.
Reference: PAGE 33 (2025) Abstr 11608 [www.page-meeting.org/?abstract=11608]
Poster: Drug/Disease Modelling - Paediatrics