Population pharmacokinetic-pharmacodynamic modeling of acetaminophen in preterm neonates with hemodynamically significant patent ductus arteriosus

Background: Pharmacokinetics (PK) of intravenous acetaminophen has not been assessed in preterm neonates with hemodynamically significant patent ductus arteriosus (PDA). Moreover, there is a lack of data evaluating the association between PK and pharmacodynamics (PD) of acetaminophen in hemodynamically significant PDA. Hence, we performed a population PK-PD modeling of acetaminophen in preterm neonates with hemodynamically significant PDA. Methods: A prospective, observational study was carried out in preterm neonates with hemodynamically significant PDA receiving intravenous acetaminophen (15 mg/kg six hourly) for maximum of nine days. The diameter of the ductus arteriosus was measured using General Electric Vivid 7® (echocardiography) and was the PD measure. The PK-PD modeling was performed using Monolix 2019R2. We performed Monte Carlo (MC) simulations to determine the probability of ductus arteriosus closure from first to the ninth day of acetaminophen treatment. Results: Fifty-five neonates were recruited. A one-compartment model with first-order elimination described well the PK of acetaminophen. Clearance (CL) and volume of distribution (Vd) for typical neonate weighing 0.98 kg was 0.0452 L/h and 1.18 L, respectively. A combination of an Imax model with effect compartment and an exponential disease progression model described well the PD of acetaminophen. The average baseline diameter of the ductus arteriosus (E0) was 2.53 mm while IC₅₀ was 0.477 µg/mL. The disease progression rate constant (Kprog) and effect compartment transfer rate constant (ke0) were 0.00425 h⁻¹ and 0.000103 h⁻¹, respectively. MC simulations of the current dosing regimen revealed a probability of 73.7% ductus arteriosus closure compared to 83.8% with 20 mg/kg six hourly dose. Conclusion: The PK-PD model developed can be used for dosing acetaminophen in premature neonates with hemodynamically significant PDA. Intravenous dose of 20 mg/kg intravenously every six hours is likely to provide a better therapeutic effect than the existing dosing regimen.