Population pharmacokinetic analysis of Ibuprofen enantiomers in preterm newborn infants

J Clin Pharmacol. 2008 Dec;48(12):1460-8. doi: 10.1177/0091270008323752. Epub 2008 Sep 16.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Anti-Inflammatory Agents, Non-Steroidal / chemistry
  • Anti-Inflammatory Agents, Non-Steroidal / pharmacokinetics
  • Area Under Curve
  • Chromatography, High Pressure Liquid
  • Clinical Trials as Topic
  • Dose-Response Relationship, Drug
  • Female
  • Half-Life
  • Humans
  • Ibuprofen / chemistry
  • Ibuprofen / pharmacokinetics*
  • Infant, Newborn
  • Infant, Premature / metabolism*
  • Male
  • Metabolic Clearance Rate
  • Models, Biological*
  • Monte Carlo Method
  • Research Design
  • Software
  • Stereoisomerism

Substances

  • Anti-Inflammatory Agents, Non-Steroidal
  • Ibuprofen