PII-072 - PHARMACOKINETICS AND PHARMACODYNAMICS MODELING OF ACETAMINOPHEN AND IBUPROFEN TO EVALUATE THE TIME TO PATENT DUCTUS ARTERIOSUS CLOSURE IN PRETERM NEONATES.

M. Almoslem^1,2, S. Shah³, S. Guzy¹, V. Vozmediano⁴, S. Kim⁴, M. Hudak³, S. Schmidt¹; ¹University of Florida, Orlando, FL, USA, ²University of Ha'il, Ha'il, Kingdom of Saudi Arabia, ³University of Florida College of Medicine - Jacksonville, Jacksonville, FL, USA, ⁴University of Florida, Gainesville, FL, USA.

Background: The ductus arteriosus is an opening in the heart that connects the aorta and the main pulmonary artery allowing the fetal blood to bypass the lungs and flow back to the systemic circulation. The prolongation of the opening leads to patent ductus arteriosus (PDA), a condition associated with mortality and severe morbidities. While ibuprofen and indomethacin (i.e., drugs currently approved by FDA for this indication) can lower early pulmonary complications, they do not improve overall mortality and are associated with renal complications. Evidence suggests that the coadministration of acetaminophen may reduce the repeated ibuprofen doses and the need for surgical ligation, thus, improving its safety and efficacy profiles. The objective of this research was to identify the optimal ibuprofen and acetaminophen treatment regimen required for timely PDA closure in preterm neonates.

Methods: We established a database summarizing dose-ranging clinical data from the literature, which was then analyzed with a time-to-event pharmacokinetic/pharmacodynamic model1,2,3.

Results: The developed model described the spontaneous time to PDA closure in preterm neonates and the effect of acetaminophen and ibuprofen plasma concentrations on PDA when given alone in different populations. Our results suggest that ibuprofen and acetaminophen reached 0.9 and 0.61 maximum inhibition effect (Imax) on time to PDA closure, respectively. The results further suggest that the time to initiate therapy played a major role in successful PDA closure.

Conclusion: The model will be utilized to simulate the coadministration of ibuprofen plus acetaminophen in different pharmacodynamic interaction scenarios (i.e., antagonistic, additive, and synergistic) to support the design of a prospective dose optimization trial in preterm neonates.

1- Bouazza, N. et al. Pharmacokinetics of Intravenous Paracetamol (Acetaminophen) and Ductus Arteriosus Closure After Premature Birth. Clin Pharmacol Ther. 2021;110(4):1087-1095.
2- Lu J, Li Q, Zhu L, Chen C, Li Z. Oral ibuprofen is superior to oral paracetamol for patent ductus arteriosus in very low and extremely low birth weight infants. Medicine (Baltimore). 2019;98(31):e16689.
3- Slaughter, J.L. et al. Early prediction of spontaneous Patent Ductus Arteriosus (PDA) closure and PDA-associated outcomes: a prospective cohort investigation. BMC Pediatr. 2019;19(1):333. 2019 Sep 13.