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Population Pharmacokinetic Analysis of Ibuprofen Enantiomers in Preterm Newborn Infants

From INSERM ERI 23 Pôle Biologie Santé, Poitiers, France (Dr Gregoire); Service de néonatologie, Hôpital Louis Mourier, Assistance Publique Hôpitaux de Paris, Colombes, France (Dr Desfrere); INSERM, CIC 004, Department of Neonatology, University Hospital of Nantes, France (Dr Pr Roze); Orphan Europe, Paris La Défense, France (Dr Kibleur); and Department of Neonatology, Charité, Campus Virchow Hospital, University Medicine Berlin, Berlin, Germany (Dr Koehne).

The aim of this pharmacokinetic analysis was to develop and validate a population pharmacokinetic model for R- and S-ibuprofen from samples obtained after 3 successive administrations of ibuprofen (10-5-5 mg/kg) at 24-hour intervals to preterm newborn infants aged from <6 hours to 8 days of life. A model including unilateral bioconversion of R-ibuprofen into S-ibuprofen was developed using the software NONMEM. R- and S-ibuprofen plasma concentrations were adequately fitted by this model. Estimated clearance and volume of distribution were 3.5 mL/h/kg and 173 mL/kg, respectively, with a calculated half-life (t) of 34.3 hours for S-ibuprofen. Estimated clearance at birth and volume of distribution were 25.5 mL/h/kg and 306 mL/kg with a t at birth of 8.3 hours for R-ibuprofen. R-ibuprofen elimination increased during the first week of life, whereas S-ibuprofen pharmacokinetics were weakly modified. Therefore, because the activity of the 2 enantiomers differs, it is important that subsequent studies consider R- and S-enantiomers separately. Mean simulated ibuprofen concentrations at various dose regimens were in agreement with observed concentrations. The present analysis allows a more accurate estimation of the ibuprofen pharmacokinetics as parameters could be estimated separately for each enantiomer and the effect of postnatal age on the elimination of R-ibuprofen was elicited.

Key Words: Population pharmacokinetics • preterm newborn infants • ibuprofen enantiomers

Address for reprints: Nicolas Gregoire, INSERM ERI 23 Pôle Biologie Santé, 40 av du Recteur Pineau 86021, Poitiers, France; e-mail: nicolas.gregoire{at}etu.univ-poitiers.fr.

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