Development of population pharmacokinetic models and optimal sampling times for ibuprofen tablet and suspension formulations in children with cystic fibrosis.

Abstract

High-dose ibuprofen therapy has demonstrated to slow deterioration in pulmonary function in children with cystic fibrosis with mild lung disease. Therapeutic drug monitoring has been recommended to maintain peak concentrations within the range of 50 to 100 mg/L to ensure efficacy. Current methods for dosage individualization are based on dose proportionality using visual inspection of the peak concentration; however, because of interpatient variability in the absorption of the various formulations this method may result in incorrect assessments of the peak concentration achieved. Maximum a posteriori Bayesian analysis (MAP-B) has proven to be a useful and precise method of individualizing the dose of aminoglycosides but requires a description of the structural model. In this study we performed parametric population modeling analysis on plasma concentrations of ibuprofen after single doses of 20 to 30-mg/kg tablet or suspension in children with cystic fibrosis. Patients evaluated in this study were part of a single dose pharmacokinetic study that has been published previously. A one-compartment model with first order absorption and a lag time best described the data. The pharmacokinetic parameters differed significantly depending on the formulation administered. D-optimal sampling times for the suspension and tablet formulations are 0, 0.25 to 0.5, 1, and 3 to 4 hours and 0, 0.25 to 0.5, 1 to 1.5, and 5 hours respectively. Use of MAP-B analysis performed with the 4 d-optimal sampling strategy resulted in accurate and precise estimates of the pharmacokinetic parameters when compared with maximum likelihood analysis using the complete plasma concentrations data set. Further studies are needed to evaluate the performance of these models and the impact on patient outcomes.