Ibuprofen enantiomers in premature neonates with patent ductus arteriosus: Preliminary data on an unexpected pharmacokinetic profile of S(+)‐ibuprofen

Abstract

S(+)-ibuprofen (S-IBU) and R(−)-ibuprofen (R-IBU) concentrations were measured in 16 neonates with patent ductus arteriosus during a cycle of therapy (three intravenous doses of 10-5-5 mg kg −1 at 24-h intervals), at the end of the first infusion and 6, 24, 48, and 72 h later. Data were analyzed with a PK model that included enantiomer elimination rate constants and the R-to S-IBU conversion rate constant. The T½ of S-IBU in the newborn was much longer than in adults (41.8 vs. ≈2 h), whereas the T½ of R-IBU appeared to be the same (2.3 h). The mean fraction of R-to S-IBU conversion was much the same as in adults (0.41 vs. ≈0.60). S-IBU concentrations measured 6 h after the first dose were higher than at the end of the infusion in 10 out of 16 cases, and in five cases, they remained higher even after 24 h. This behavior is unprecedented and may be attributable to a rapid R-to-S conversion overlapping with a slow S-IBU elimination rate. In 13 of the 16 neonates, S-IBU concentrations at 48 and/or 72 h were lower than expected, probably due to the rapid postnatal maturation of the newborn's liver metabolism.

Oral Ibuprofen Is More Effective than Intravenous Ibuprofen for Closure of a Patent Ductus Arteriosus: Can Pharmacokinetic Modeling Help Us to Understand Why?

“…One PK study in 108 neonates treated with IV ibuprofen reported a low systemic R- to S-conversion rate of 17% [10]. A second study in 16 neonates where ibuprofen was administered IV in a 10-5-5 mg/kg dose schedule found evidence for enantiomeric conversion with a mean rate of 41%, albeit with a wide range (7–87%) [20].…”

“…However, the evidence on enantiomeric conversion in neonates is rather weak. While numerous studies report fractions of the dose undergoing enantiomeric conversion of around 60% in adults [16][17][18][19], conflicting results are reported for conversion in neonates with fractions varying from 0 to 61% [9][10][11]20].…”