Intravenous acetaminophen (at 15 mg/kg/dose every 6 hours) in critically ill preterm neonates with patent ductus arteriosus: A prospective study.

WHAT IS KNOWN AND OBJECTIVES: Acetaminophen has been increasingly used in treating patent ductus arteriosus (PDA) in preterm neonates. Variations were observed in the dosing regimen of acetaminophen across the studies. There is hardly any data available for a relatively higher dose of intravenous acetaminophen (15 mg/kg/dose every 6 hours) in the preterm population. We present here the results of a prospective study with this dose of intravenous acetaminophen for treating PDA in critically ill preterm neonates. METHODS: Preterm neonates (≤37 weeks of gestational age) with haemodynamically significant PDA were enrolled. Intravenous acetaminophen at 15 mg/kg/dose every 6 hours was administered. Echocardiographic monitoring, liver and renal function tests were carried out. Standard definitions were adhered for defining acute kidney injury (AKI) and hepatotoxicity. RESULTS: Fifty-five neonates were recruited. Following the first dose, less than half had their serum acetaminophen concentrations in the therapeutic range. Extreme preterm neonates were less likely to have a sustained therapeutic acetaminophen concentration after the first dose. Following multiple doses and at steady state, 97.2% and 98.8% respectively were in the therapeutic range. Forty-three (78.2%) neonates had successful closure of the ductus arteriosus of which 22 were extreme preterm, 17 were very preterm and 4 were late preterm neonates; and considering their birthweights, 21 were extremely low, 16 were very low and 6 were low birthweight categories. Ten neonates had elevated alanine aminotransferase levels with three in the low-to-moderate risk of hepatotoxicity category. Eight neonates had altered renal function tests indicating AKI. WHAT IS NEW AND CONCLUSION: Intravenous acetaminophen at 15 mg/kg/dose every 6 hours was efficacious in 78.2% of the preterm neonates with PDA. We observed a lower incidence of hepatotoxicity, and AKI in the study population. No association was observed between the serum acetaminophen concentrations and PDA closure.

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.