Ibuprofen Pharmacokinetics in Premature Infants with Patent Ductus Arteriosus

Abstract 1352 Poster Session I, Saturday, 5/1 (poster 58)

Introduction: Ibuprofen seems to be a reasonable alternative for treatment of patent ductus arteriosus in premature infants with possibly less renal side effects and offering some cerebrovascular protection, as compared to indomethacin. Pharmacokinetic data are scarce and conflicting.

Objective: To investigate pharmacokinetics and possible changes in pharmacokinetic parameters of intravenous ibuprofen in premature infants with patent ductus arteriosus.

Patients and methods: In 27 premature infants (gestational age: 28.6 ±2.2 wks, birthweight: 1250 ± 460 g, mean ±SD) with respiratory distress syndrome, with an echocardiographically proven hemodynamically significant patent ductus arteriosus and without renal insufficiency, pharmacokinetics were investigated after a 15-minute i.v. ibuprofen-lysine infusion (10-5-5 mg/kg, at 24 hr intervals) after the first dose (day 3 of life) and after the third dose (day 5 of life). Samples were drawn from an arterial catheter (0.4mL/sample) at 30 min, 1, 2, 4, 12 and 24 hrs after infusion. Renal function and closure of the ductus was registered. Ibuprofen serumconcentrations were determined by HPLC-assay.

Results: Ibuprofen pharmacokinetics followed a two-compartment open model. Peak serum concentrations 1 hr after the first and third dose were 33.3 ± 8.5 and 28.4 ± 9.2 mg/L (mean ±1 SD). The total body clearance of ibuprofen (8.3 vs 10.9 mL/hr, p<0.03, paired t-test) and the elimination rate constant (0.036 vs 0.087 L/kg, p=0.05) increased significantly, whereas the serum half-life (37 vs 27 hrs) and the apparent volume of distribution (0.21 vs 0.15 L/kg) tended to decrease between day 3 and day 5 after birth during ibuprofen treatment. In patients with closed ductus arteriosus after treatment, the ibuprofen peak and through serumconcentrations were higher after the third dose as compared to patients with persistent ductus after treatment (18.7 ± 10.8 vs 6.3 ± 3.6 mg/L, p=0.05). The ductus closed in 17 of 27 patients (63%). Renal function, objectivated by urine production, serum creatinine values and serum creatinine clearance, did not change significantly in any of the patients after the administration of ibuprofen.

Conclusion: These results indicate that the pharmacokinetics of ibuprofen show significant changes between day 3 and day 5 after birth in preterm infants with a patent ductus arteriosus, caused by maturational effects and/or closure of the duct, and that an ibuprofen serumconcentration above 10 mg/mL is associated with a higher closure rate.

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Van Overmeire, B., Schepens, P., Langhendries, J. et al. Ibuprofen Pharmacokinetics in Premature Infants with Patent Ductus Arteriosus. Pediatr Res 45, 230 (1999). https://doi.org/10.1203/00006450-199904020-01369

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