Population Pharmacokinetic Analysis of Ibuprofen Enantiomers in Preterm Newborn Infants

Abstract

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.

Cardio-respiratory Events and Inflammatory Response After Primary Immunization in Preterm Infants < 32 Weeks Gestational Age: A Randomized Controlled Study

“…In addition, all post-immunization measurements were conducted at 18 hours, which potentially does not represent a similar time point in the inflammation kinetics of all patients. Further, because of the large inter individual variability in pharmacokinetics parameters of the active S (+)-ibuprofen enantiomere expected in this population of preterm infants 30 , we cannot exclude the possibility that the drug concentrations were not sufficient to significantly reduce PgE2 levels in a proportion of infants, while sufficient to mitigate the CRE elevation response to immunization. We are not aware of other studies reporting measures of PgE2 after immunization in infants.…”

Renal Side Effects of Non-Steroidal Anti-Inflammatory Drugs in Neonates

“…Similarly, adaptations in either the route of administration (oral versus intravenous) or the use of enantiomer specific solutions have to be evaluated on their potential benefits compared to the currently implemented dosing regimes [36,37]. Others reported on the improved renal tolerance to indomethacin when continuous administration was compared to intermittent ‘bolus’ administration [38].…”

Simulation-based suggestions to improve ibuprofen dosing for patent ductus arteriosus in preterm newborns

“…The population PK models (see Supplementary File 1) were compared with respect to birth weight, gestational age (GA), and postnatal age (PNA) of the cohort, ibuprofen-dosing regimen, route of administration, and studied ibuprofen enantiomers [12, 22, 23, 30, 31]. …”