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

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 I_max 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 (I_max) parameters. Two subpopulations with different I_max 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.