title: Plasma and cerebrospinal fluid concentrations of ibuprofen in pediatric patients and antipyretic effect: Pharmacokinetic-pharmacodynamic modeling analysis.
abstract: 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 10.0 mg/kg; 3.4-11.4 mg/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 (CCSF /Cplasma ) 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.
authors.affiliation: Pediatric Emergency Unit, Clinical Pharmacology & Toxicology Unit and Pediatric Ward B, Assaf Harofeh Medical Center, Zerifin, Israel.
authors.forename: Ronly
authors.initials: R
authors.lastname: Har-Even
authors.forename: David
authors.initials: D
authors.lastname: Stepensky
authors.forename: Malka
authors.initials: M
authors.lastname: Britzi
authors.forename: Stefan
authors.initials: S
authors.lastname: Soback
authors.forename: Adina Bar
authors.initials: AB
authors.lastname: Chaim
authors.forename: Norit
authors.initials: N
authors.lastname: Brandriss
authors.forename: Michael
authors.initials: M
authors.lastname: Goldman
authors.forename: Matitiahu
authors.initials: M
authors.lastname: Berkovitch
authors.forename: Eran
authors.initials: E
authors.lastname: Kozer
mesh_terms: D000293:Adolescent; D058633:Antipyretics / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000494:pharmacology; D001831:Body Temperature / Q000187:drug effects*; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007052:Ibuprofen / Q000097:blood / Q000134:cerebrospinal fluid / Q000493:pharmacokinetics / Q000494:pharmacology; D007223:Infant; D008297:Male; D008954:Models, Biological
chemical_list: D058633:Antipyretics; D007052:Ibuprofen
keywords: drug concentrations in plasma and cerebrospinal fluid; ibuprofen antipyretic effect; infants and children; pharmacokinetic-pharmacodynamic modeling