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Population Pharmacokinetics of Ibuprofen Enantiomers in Very Premature Neonates

From Aster-Cephac, Saint-Benoit, France (Dr Gregoire, Dr Gualano, Ms Geneteau, Dr Millerioux, Ms Brault, Dr Mignot) and the Department of Neonatology, University Hospital of Nantes, France (Dr Roze).

The objective of the present study was to evaluate the pharmacokinetic parameters for both S- and R-ibuprofen enantiomers in very premature neonates (gestational age strictly inferior to 28 weeks) and possible relationships between the pharmacokinetic parameters and various covariates. Newborns were randomized to receive ibuprofen or placebo for the prophylactic treatment of patent ductus arteriosus (PDA) at an initial dose of 10 mg/kg ibuprofen within 6 hours after birth, followed by two 5-mg/kg doses at 24-hour intervals (n = 52). If a PDA was still present afterwards, a curative course of ibuprofen using the same dosage regimen was administered (n = 10). A sparse sampling strategy was used because only 2 samples were collected after the third prophylactic injection and 1 after the third curative injection. A model including the chiral transformation of R- to S-ibuprofen was fitted to the concentration-time data using a population approach (NONMEM). R- and S-ibuprofen t_1/2 were about 10 hours and 25.5 hours, respectively. After prophylactic treatment, the mean clearance of R-ibuprofen (CL_R = 12.7 mL/h) was about 2.5-fold higher than for S-ibuprofen (CL_S = 5.0 mL/h). In addition, clearance of R- and S-ibuprofen increased significantly with gestational age. The mean estimation of R-ibuprofen clearance was found to be higher than for S-ibuprofen, and the clearance of both enantiomers increased with gestational age. This should be considered to assess pharmacokinetic-pharmacodynamic relationships of ibuprofen in premature neonates and subsequently to understand and refine the use of ibuprofen in managing PDA either as a prophylactic or curative treatment.

Key Words: Ibuprofen enantiomers • premature neonates • pharmacokinetics

Address for reprints: Nicolas Gregoire, Aster-Cephac 90 avenue des Hauts de la Chaume BP28 86281, Saint-Benoit, France.

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This article has been cited by other articles:

				N. Gregoire, L. Desfrere, J.-C. Roze, Y. Kibleur, and P. Koehne Population Pharmacokinetic Analysis of Ibuprofen Enantiomers in Preterm Newborn Infants J. Clin. Pharmacol., December 1, 2008; 48(12): 1460 - 1468. [Abstract] [Full Text] [PDF]

				J. V. Aranda and R. Thomas Pharmacology Review: Intravenous Ibuprofen for Preterm Newborns NeoReviews, November 1, 2005; 6(11): e516 - e523. [Full Text] [PDF]