RESUMO
Background: Gentamicin has been shown to cause vasodilation in preclinical studies. Hemodynamically significant patent ductus arteriosus (hsPDA) is a commonly observed congenital heart disorder in preterm neonates. Concomitant gentamicin theoretically shall delay the closure/result in nonclosure of ductus arteriosus (DA). Similarly, hsPDA can alter the pharmacokinetics of gentamicin and so trough gentamicin concentrations. We carried out the present study to evaluate the association between gentamicin use and closure of hsPDA (treated with acetaminophen) as well as the effect of hsPDA on trough concentrations. Methods: This study was a prospective, observational study that included 60 neonates diagnosed with hsPDA by echocardiography and 102 neonates without hsPDA. Demographic details, size of DA as per echocardiography at the end of treatment with acetaminophen, gentamicin-dosing regimen, and trough concentrations were collected. Standard definitions were adhered in classifying the gestational age, birth weights, and size of DA. The numerical values are reported in median (range). Results: Neonates with hsPDA had significantly lower daily doses of gentamicin [4.5 (2.5-10), 7 (3.2-13) mg; P < 0.001] but longer duration of therapy [8 (3-14), 5 (3-7) days; P < 0.001] than those without hsPDA in very preterm neonates. No significant differences were observed in the trough concentrations of gentamicin between the groups. No association was observed between gentamicin use and closure of DA. However, those with successful closure of DA received gentamicin for a longer duration [6 (3-10), 4 (3-14) days; P < 0.05] that was independent of acetaminophen duration and had received higher cumulative doses of gentamicin. Conclusion: In conclusion, we observed a significantly longer duration of gentamicin therapy in neonates with hsPDA compared to those without hsPDA. No significant differences were observed in the rates of closure of DA with concomitant gentamicin administration and gentamicin trough concentrations.
RESUMO
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.
