title: Population pharmacokinetics of phenytoin in critically ill children.
abstract: The objective was to study the population pharmacokinetics of bound and unbound phenytoin in critically ill children, including influences on the protein binding profile. A population pharmacokinetic approach was used to analyze paired protein-unbound and total phenytoin plasma concentrations (n = 146 each) from 32 critically ill children (0.08-17 years of age) who were admitted to a pediatric hospital, primarily intensive care unit. The pharmacokinetics of unbound and bound phenytoin and the influence of possible influential covariates were modeled and evaluated using visual predictive checks and bootstrapping. The pharmacokinetics of protein-unbound phenytoin was described satisfactorily by a 1-compartment model with first-order absorption in conjunction with a linear partition coefficient parameter to describe the binding of phenytoin to albumin. The partitioning coefficient describing protein binding and distribution to bound phenytoin was estimated to be 8.22. Nonlinear elimination of unbound phenytoin was not supported in this patient group. Weight, allometrically scaled for clearance and volume of distribution for the unbound and bound compartments, and albumin concentration significantly influenced the partition coefficient for protein binding of phenytoin. The population model can be applied to estimate the fraction of unbound phenytoin in critically ill children given an individual's albumin concentration.
authors.affiliation: School of Pharmacy, Pharmacy Australia Centre of Excellence (PACE), The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Hennig
authors.affiliation: School of Pharmacy, Pharmacy Australia Centre of Excellence (PACE), The University of Queensland, Brisbane, Queensland, Australia.|Australian Centre for Paediatric Pharmacokinetics, Mater Pathology Services and Mater Research Institute, Brisbane, Queensland, Australia.|School of Pharmacy, Griffith University, Gold Coast, Queensland, Australia.
authors.forename: Ross
authors.initials: R
authors.lastname: Norris
authors.affiliation: Mater Pharmacy Services, Mater Health Services, Brisbane, Queensland, Australia.
authors.forename: Quyen
authors.initials: Q
authors.lastname: Tu
authors.affiliation: Australian Centre for Paediatric Pharmacokinetics, Mater Pathology Services and Mater Research Institute, Brisbane, Queensland, Australia.
authors.forename: Karin
authors.initials: K
authors.lastname: van Breda
authors.affiliation: Neurosciences Unit, Mater Children's Hospital, Brisbane, Queensland, Australia.|Mater Medical Research Institute, University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Riney
authors.affiliation: Acute Care Stream, West Moreton Hospital and Health Service, Ipswich, Queensland, Australia.
authors.forename: Kelly
authors.initials: K
authors.lastname: Foster
authors.affiliation: Paediatric Intensive Care Unit, Mater Children's Hospital, Brisbane, Queensland, Australia.|Medical School, Griffith University, Gold Coast, Queensland, Australia.
authors.forename: Bruce
authors.initials: B
authors.lastname: Lister
authors.affiliation: School of Pharmacy, Pharmacy Australia Centre of Excellence (PACE), The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Bruce
authors.initials: B
authors.lastname: Charles
mesh_terms: D000293:Adolescent; D000367:Age Factors; D000927:Anticonvulsants / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D002648:Child; D002675:Child, Preschool; D016638:Critical Illness; D005260:Female; D006776:Hospitals, Pediatric; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D015278:Intensive Care Units, Pediatric; D016014:Linear Models; D008297:Male; D008954:Models, Biological; D017711:Nonlinear Dynamics; D010672:Phenytoin / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011485:Protein Binding
chemical_list: D000927:Anticonvulsants; D010672:Phenytoin
keywords: critical care; pediatrics; phenytoin; population pharmacokinetics; protein binding