title: The quantitative effect of serum albumin, serum urea, and valproic acid on unbound phenytoin concentrations in children.
abstract: Dosing of phenytoin is difficult in children because of its variable pharmacokinetics and protein binding. Possible covariates for this protein binding have mostly been univariately investigated in small, and often adult, adult populations. We conducted a study to identify and quantify these covariates in children. We extracted data on serum phenytoin concentrations, albumin, triglycerides, urea, total bilirubin and creatinine concentrations and data on coadministration of valproic acid or carbamazepine in 186 children. Using nonlinear mixed effects modeling the effects of covariates on the unbound phenytoin fraction were investigated. Serum albumin, serum urea concentrations, and concomitant valproic acid use significantly influenced the unbound phenytoin fraction. For clinical practice, we recommend that unbound phenytoin concentrations are measured routinely. However, if this is impossible, we suggest to use our model to calculate the unbound concentration. In selected children, close treatment monitoring and dose reductions should be considered to prevent toxicity.
authors.affiliation: Department of Clinical Pharmacy, Meander Medical Centre, Amersfoort, The Netherlands rob@terheine.nl.
authors.forename: Rob
authors.initials: R
authors.lastname: ter Heine
authors.affiliation: Department of Clinical Pharmacy, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Erik M
authors.initials: EM
authors.lastname: van Maarseveen
authors.affiliation: Department of Clinical Pharmacy, Meander Medical Centre, Amersfoort, The Netherlands.
authors.forename: Monique M L
authors.initials: MM
authors.lastname: van der Westerlaken
authors.affiliation: Department of Child Neurology, Rudolf Magnus institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Kees P J
authors.initials: KP
authors.lastname: Braun
authors.affiliation: Department of Child Neurology, Rudolf Magnus institute of Neuroscience, University Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Koudijs
authors.affiliation: Department of Clinical Chemistry and Hematology, Medical Centre Utrecht, Utrecht, The Netherlands.
authors.forename: Maarten J Ten
authors.initials: MJ
authors.lastname: Berg
authors.affiliation: Department of Clinical Pharmacy, Meander Medical Centre, Amersfoort, The Netherlands.
authors.forename: Mirte M
authors.initials: MM
authors.lastname: Malingré
mesh_terms: D000293:Adolescent; D000927:Anticonvulsants / Q000494:pharmacology / Q000627:therapeutic use; D001663:Bilirubin / Q000097:blood; D002220:Carbamazepine / Q000494:pharmacology* / Q000627:therapeutic use; D002648:Child; D002675:Child, Preschool; D016208:Databases, Factual / Q000706:statistics & numerical data; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009426:Netherlands; D017711:Nonlinear Dynamics; D010672:Phenytoin / Q000097:blood / Q000494:pharmacology* / Q000627:therapeutic use; D011485:Protein Binding / Q000187:drug effects; D012189:Retrospective Studies; D012709:Serum Albumin / Q000378:metabolism*; D014508:Urea / Q000097:blood*; D014635:Valproic Acid / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000927:Anticonvulsants; D012709:Serum Albumin; D002220:Carbamazepine; D014635:Valproic Acid; D010672:Phenytoin; D014508:Urea; D001663:Bilirubin
keywords: albumin; bilirubin; carbamazepine; phenytoin; urea; valproic acid