Spontaneous closure of the ductus arteriosus depends on gestational age (GA) and might be delayed in preterm infants, resulting in
patent ductus arteriosus (PDA).
Ibuprofen can be administered to enhance closure, but the exposure-response relationship between
ibuprofen and the closure of PDA remains uncertain. We investigated the influence of patient characteristics and
ibuprofen exposure on ductus closure. A cohort of preterm infants with PDA and treated with
ibuprofen was analyzed.
Ibuprofen exposure was based on a previously developed population pharmacokinetic study that was in part based on the same study population. Logistic regression analyses were performed with ductus closure (yes/no) as outcome, to analyze the contribution of
ibuprofen exposure and patient characteristics. In our cohort of 263 preterm infants (median GA 26.1 (range: 23.7-30.0) weeks,
birthweight 840 (365-1,470) g) receiving
ibuprofen treatment consisting of 3 doses that was initiated at a median postnatal age (PNAstart ) of 5 (1-32) days, PDA was closed in 55 (21%) patients. Exposure to
ibuprofen strongly decreased with PNAstart . Overall, the probability of ductus closure decreased with PNAstart (odds ratio (OR): 0.7, 95% CI: 0.6-0.8) and Z-score for
birthweight (ZBirthweight-for-GA ; OR: 0.8, 95% CI: 0.6-1.0), and increased with GA (OR: 1.5, 95% CI: 1.1-1.9). For patients with PNAstart < 1 week, concentrations of
ibuprofen, GA, and ZBirthweight-for-GA predicted probability of ductus closure. During a window of opportunity for ductus closure within the first days of life, probability of closure depends on GA, ZBirthweight-for-GA , and
ibuprofen exposure. Increased, yet unstudied dosages might increase the effectivity of
ibuprofen beyond the first week of life.