(W-013) Patent Ductus Arteriosus in Preterm Infants: Exploring Optimal Acetaminophen Dosing for Oral and Rectal Administration

Kannan Sridharan, MD, DM – Associate Professor, Department of Pharmacology & Therapeutics,, College of Medicine and Medical Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain; Mathangi Gopalakrishnan, MS, PhD – Assistant Professor, Center for Translational Medicine,School of Pharmacy, University of Maryland , Baltimore

Objectives: Hemodynamically significant patent ductus arteriosus (PDA) poses significant challenges in neonatal care, especially for preterm infants, and can lead to complications such as pulmonary hemorrhage and necrotizing enterocolitis, accounting for about 10% of congenital heart disease cases¹. Current treatments include invasive surgery or the use of non-steroidal anti-inflammatory drugs which are associated with acute kidney injury. Recently, intravenous (IV) acetaminophen (APAP) has emerged as a potential first-line drug for PDA due to its widespread use in neonates. However, oral and rectal dosing might be more favorable route of administration than IV APAP. Thus, the main goal of this research was to leverage an existing pharmacokinetic–pharmacodynamic (PK-PD) model of APAP to perform simulations to inform dosing regimens for oral and rectal route.

Methods: We used a one-compartment PK model of APAP² which was based on pooled data from 283 pediatric subjects (124 aged < 6 months), with median postconceptional age 40 weeks(range:28-64). This model described the PK of APAP administered orally or rectally adjusting for gestational age. We integrated this PK model with a distributional delay PK-PD model³, previously developed using data from a prospective trial of 55 preterm neonates with PDA receiving IV APAP at 15 mg/kg every 6 hours (q6h). The PD outcome was ductus arteriosus diameter (mm). The integrated PK-PD model was used to simulate q6h oral and rectal dosing regimens for different gestational ages (30-36 weeks). Each scenario included 1000 virtual patients, with PDA closure defined as ductus size < 0.1 mm. Regimens were assessed based on the proportion of neonates achieving ductus closure on day 9 and compared to the IV dosing regimen. Simulations were performed using Pumas V2.4.

Results: Enteral routes necessitated gestational age-adjusted dosing as maturation factors affect absorption parameters of APAP. Simulations showed that achieving at least 70% PDA closure on day 9 required a steady-state trough concentration C_trough,ss >37 mg/L. For oral elixirs, doses escalated from 25 to 45 mg/kg with gestational age and achieved 77% to 81% closure rates. Rectal capsules, solutions, and triglycerides required higher dosages, achieving 71% to 83% closure rates with doses ranging from 27.5 to 65 mg/kg. Despite C_trough,ss levels exceeding the typical target of 10 μg/mL for APAP, the incidence of hepatotoxicity can be expected to be relatively low as shown by Sridharan et al.3, where the median steady-state concentration of APAP was 48 μg/mL.

Conclusion: By leveraging information from prior PK-PD models of IV APAP, dosing regimens of oral and rectal administration of APAP that achieved at least 70% PDA closure were proposed for preterm neonates with PDA by simulations to inform future clinical trials in this vulnerable population.

Citations: 1. Brickner ME, Hillis LD, Lange RA. Congenital Heart Disease in Adults. N Engl J Med. 2000;342(4):256-263. doi:10.1056/NEJM200001273420407

2. Anderson BJ, Lin YC. Acetaminophen Developmental Pharmacokinetics in Premature Neonates and Infants. 2002;96(6).

3. Sridharan K, Ansari EA, Mulubwa M, et al. Population pharmacokinetic-pharmacodynamic modeling of acetaminophen in preterm neonates with hemodynamically significant patent ductus arteriosus. European Journal of Pharmaceutical Sciences. 2021;167:106023. doi:10.1016/j.ejps.2021.106023