Pharmacokinetics of ibuprofen in premature infants

As reassuring evidence of clinical outcomes emerges it is important to improve our understanding of the disposition of ibuprofen in premature infants.

Two recent studies have explored the pharmacokinetics of oral and intravenous ibuprofen in premature (gestational age 30 weeks)7 and very premature (24 - 28 weeks)8 infants. Both reported wide interindividual variation in plasma levels and clearance of ibuprofen. Overall, clearance increased with gestational age and birth weight, though the correlation was weak. Neither study identified factors that might lead to more predictable blood levels.

Despite the variation in blood levels, the likelihood of adverse renal effects seems low, according to investigators in Israel9. In 15 low-birth weight infants (mean 1.05 kg, mean gestational age 27.5 weeks) with PDA, they found no changes in renal function or urine output at 24 or 48 hours during treatment with the usual doses of ibuprofen.

An important concern about the use of ibuprofen in neonates is the risk of kernicterus due to displacement of bilirubin from its binding sites on albumin. An in vitro study has shown that ibuprofen competes with bilirubin for these binding sites, and that the displacement of bilirubin could be greater than that of the sulfonamide sulfasoxazole10. Fortunately, this does not appear to be clinically significant: a study in 15 preterm infants showed no change in the concentration of unbound bilirubin in plasma after the administration of ibuprofen at the doses used to treat PDA11.

Another concern is the risk of drug interactions. Although no clinical effects were reported in infants treated with ibuprofen plus vitamin K, phenobarbitone, or the antibiotics netilmicin, amikacin, or cefotaxime7, more careful analysis of the pharmacokinetics of amikacin during prophylaxis of PDA with ibuprofen-lysine suggests that clearance of the antibiotic is significantly reduced and pre-dose blood levels of amikacin were raised12. The authors note that levels of both amikacin and ibuprofen were too high in these infants and suggested increasing the dose intervals for both drugs.

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