Plasma and cerebrospinal fluid concentrations of ibuprofen in pediatric patients and antipyretic effect: Pharmacokinetic-pharmacodynamic modeling analysis

We aimed to determine the relationship between plasma and cerebrospinal fluid (CSF) concentrations of ibuprofen and the antipyretic effect in pediatric patients. A prospective cohort of infants and children aged 3 months to 15 years and treated with ibuprofen was studied. The patients received ibuprofen (via oral route, median dose of 10.0mg/kg; 3.4-11.4mg/kg range), samples of blood and CSF were collected, and body temperature was measured. Sequential analysis of the pharmacokinetic and pharmacodynamic data from 28 patients was performed using a population modeling approach. The observed concentration versus time data indicated substantial pharmacokinetic variability in absorption and distribution of ibuprofen between the patients. The pharmacokinetic modeling outcomes indicate that following a ∼25-minute lag time, ibuprofen is rapidly absorbed to the central compartment and rapidly equilibrates with the CSF, resulting in the total ibuprofen concentration in the CSF versus plasma (C _CSF/C_plasma) of 0.011±0.007. The antipyretic effect of ibuprofen was best described by an indirect response PK-PD model incorporating patient baseline body temperature and ibuprofen concentration in the CSF. We conclude that the pharmacokinetic-pharmacodynamic modeling can be used to predict the time course of ibuprofen plasma and CSF concentrations and of the antipyretic effects in individual pediatric patients.