Aline G.J. Engbers (1,2), Swantje Völler (1), Robert B. Flint (2,3), Sebastiaan C. Goulooze (4), Johan de Klerk (2), Elke H.J. Krekels (1), Monique van Dijk (5) , Sten Willemsen (6), Irwin K.M. Reiss (2), Catherijne A.J. Knibbe (1,2,7), Sinno H.P. Simons (2)
(1) Division of Systems Pharmacology and Pharmacy, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands, (2) Department of Paediatrics, Division of Neonatology, Erasmus UMC - Sophia Children’s Hospital, Rotterdam, the Netherlands, (3) Department of Hospital Pharmacy, Erasmus University Medical Center, Rotterdam, the Netherlands, (4) Leiden Experts on Advanced Pharmacokinetics and Pharmacodynamics (LAP&P), Leiden, The Netherlands, (5) Department of Pediatric Surgery, Erasmus UMC - Sophia Children’s Hospital, Rotterdam, the Netherlands, (6) Department of Biostatistics, Division of Neonatology, Erasmus UMC - Sophia Children’s Hospital, Rotterdam, the Netherlands, (7) Department of Clinical Pharmacy, St Antonius Hospital, Nieuwegein, the Netherlands
Objectives: In term born neonates the ductus arteriosus closes spontaneously within hours after birth, partly due to a drop in prostaglandin E2 (PGE2). In prematurely born neonates spontaneous closure is often delayed due to an increased sensitivity to PGE2[1]. It is well known that the risk for patent ductus arteriosus (PDA) increases with lower gestational age at birth. Ibuprofen is the most frequently used drug to stimulate closure of the PDA via cyclo-oxygenase inhibition resulting in a decrease in PGE2 production.
Historically, a 3-day dosing regimen of 10-5-5 mg/kg ibuprofen is applied, but in a meta-analysis an oral regimen of 20-10-10 mg/kg was found most effective for PDA closure[2]. Pharmacokinetic studies on ibuprofen in preterm neonates have identified increasing clearance with postnatal age (PNA) and gestational age (GA)[3,4]. As a result, exposure to ibuprofen was found to differ between patients with varying characteristics and changes within patients due to increasing PNA. Studies on the efficacy of ibuprofen often did not include such patient characteristics[2]. Therefore, the aim of the current study was to detangle the contribution of patient characteristics, timing of treatment and ibuprofen exposure to the closure of PDA in a large population of preterm infants with varying patient characteristics and ibuprofen dosing regimens.
Methods: A clinical cohort of preterm infants with PDA and treated with ibuprofen was analysed retrospectively. Patients were treated with 10-5-5 mg/kg, 20-10-10 mg/kg, or a PNA-adapted regimen starting with 10-5-5 mg/kg gradually increasing up to 20-10-10 mg/kg. Patients were included based on intention to treat, resulting in varying GAs and PNAs at which treatment was initiated (PNAstart) for the included patients. An ultrasound was typically made after 3 doses to examine the status of the PDA, but could be postponed if the outcome was expected to be clinically irrelevant based on clinical signs. Ibuprofen treatment was repeated after 3 days if deemed necessary. Ibuprofen exposure was predicted based on a previously developed population pharmacokinetic model that was, in part, based on the same patients[4]. To determine the contribution of ibuprofen exposure, timing of treatment and patient characteristics to ductus closure, we performed logistic regression analyses with ductus closure (y/n) as outcome after three doses of ibuprofen. The complete cohort was analysed and a subgroup analysis was performed on patients with PNAstart below one week.
Results: In our cohort of 263 preterm infants (median GA 26.1 (range 23.7-30.0) weeks, birthweight 840 (365-1470) g) receiving ibuprofen treatment consisting of three doses initiated at a median PNAstart of 5 (1-32) days, PDA closed in 55 (21%) patients after 3 doses. Exposure to ibuprofen strongly decreased with increasing PNAstart. Overall, the probability of ductus closure decreased with increasing PNAstart (odds ratio (OR) 0.7 (0.6-0.8 95%CI)) and lower birthweight for GA (ZBirthweight-for-GA)(OR 0.8 (0.6-1.0 95%CI), and increased with higher GA (OR 1.5 (1.1-1.9 95%CI)). For patients with PNAstart < 1 week, ibuprofen exposure, GA, and ZBirthweight-for-GA were correlated with the probability of ductus closure.
Conclusions: In our cohort of prematurely born neonates for which treatment was initiated relatively late, closure rate was low, especially after the first week of life. There appears to be a window of opportunity for ibuprofen-induced ductus closure within the first days of life, with a probability of closure that depends on GA, birthweight-for-GA, and ibuprofen exposure. Beyond the first week of life, higher dosages, that have hitherto not been studied, might be needed to increase the exposure and thereby the probability of ibuprofen-induced closure.
References:
[1] Hundscheid T, van den Broek M, van der Lee R, et al. Understanding the pathobiology in patent ductus arteriosus in prematurity—beyond prostaglandins and oxygen. Pediatr Res 2019;86:28–38. doi:10.1038/s41390-019-0387-7
[2] Mitra S, Florez ID, Tamayo ME, et al. Association of placebo, indomethacin, ibuprofen, and acetaminophen with closure of hemodynamically significant patent ductus arteriosus in preterm infants a systematic review and meta-analysis. JAMA – J Am Med Assoc 2018;319:1221–38. doi:10.1001/jama.2018.1896
[3] Hirt D, Van Overmeire B, Treluyer JM, et al. An optimized ibuprofen dosing scheme for preterm neonates with patent ductus arteriosus, based on a population pharmacokinetic and pharmacodynamic study. Br J Clin Pharmacol 2008;65:629–36. doi:10.1111/j.1365-2125.2008.03118.x
[4] Engbers AGJ, Klerk JCA De, Flint RB, et al. Enantiomer specific pharmacokinetics of ibuprofen in preterm neonates with patent ductus arteriosus. Br J Clin Pharmacol 2020;:1–12. doi:10.1111/bcp.14298
Reference: PAGE 30 (2022) Abstr 10194 [www.page-meeting.org/?abstract=10194]
Poster: Drug/Disease Modelling - Paediatrics