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Altered Phenytoin Pharmacokinetics in Children with Severe, Acute Traumatic Brain Injury
Author(s) -
Stowe Cindy D.,
Lee Kelley R.,
Storgion Stephanie A.,
Phelps Stephanie J.
Publication year - 2000
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/009127000004001216
Subject(s) - phenytoin , pharmacokinetics , medicine , traumatic brain injury , metabolism , anticonvulsant , regimen , anesthesia , pharmacology , epilepsy , psychiatry
The purpose of this study was to determine if phenytoin protein binding and metabolism were altered in prepubescent pediatric patients within the first 10 days following severe, acute traumatic brain injury. Patients ( n = 10) received phenytoin loading doses (15–20 mg/kg) followed by a maintenance regimen (7 mg/kg/day) initiated within 12 hours of the loading dose. Phenytoin serum concentrations were measured serially on days 1, 2, 3, 5, 7, 9, and 10 at 1, 6, and 12 hours. Time‐invariant and time‐variant Michaelis‐Menten pharmacokinetic models were fit to the unbound phenytoin concentration‐time data (ADAPT II ™ ). Albumin concentrations significantly decreased over time ( p < 0.001) and were predictive of the phenytoin binding ratio ( r 2 = 0.373, p < 0.0001). The time‐variant model provided a superior fit of the data in 7 patients with no difference between models in 3 patients. Rapid inhibition of metabolism (Vmax baseline = 2.82 ± 2.35 mg/kg/day) was observed initially following injury. This was followed by induction of metabolism as reflected by a Vmax induced of 20.79 ± 13.71 mg/kg/day, which was approximately twofold higher than reported values for nonstressed children. Children with severe, acute neurotrauma were found to have markedly altered protein binding and phenytoin metabolism .