Population pharmacokinetic analysis of Ibuprofen enantiomers in preterm newborn infants.
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.
Gregoire
Nicolas
N
INSERM ERI 23 Pôle Biologie Santé, 40 av du Recteur Pineau 86021, Poitiers, France. nicolas.gregoire@etu.univ-poitiers.fr
Desfrere
Luc
L
Roze
Jean-Christophe
JC
Kibleur
Yves
Y
Koehne
Petra
P
D000465:Algorithms; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000737:chemistry / Q000493:pharmacokinetics; D019540:Area Under Curve; D002851:Chromatography, High Pressure Liquid; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D005260:Female; D006207:Half-Life; D006801:Humans; D007052:Ibuprofen / Q000737:chemistry / Q000493:pharmacokinetics*; D007231:Infant, Newborn; D007234:Infant, Premature / Q000378:metabolism*; D008297:Male; D008657:Metabolic Clearance Rate; D008954:Models, Biological; D009010:Monte Carlo Method; D012107:Research Design; D012984:Software; D013237:Stereoisomerism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D007052:Ibuprofen