Population pharmacokinetic analysis of Ibuprofen enantiomers in preterm newborn infants

Gregoire, N.; Desfrere, L.; Roze, J.-C.; Kibleur, Y.; Koehne, P.

Journal of Clinical Pharmacology 48(12): 1460-1468


ISSN/ISBN: 0091-2700
PMID: 18796580
DOI: 10.1177/0091270008323752
Accession: 055054068

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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((1/2))) 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((1/2)) 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.