Altered Phenytoin Pharmacokinetics in Children with Severe, Acute Traumatic Brain Injury

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 r...

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Bibliographic Details
Published in:Journal of clinical pharmacology 2000-12, Vol.40 (12), p.1452-1461
Main Authors: Stowe, Cindy D., Lee, Kelley R., Storgion, Stephanie A., Phelps, Stephanie J.
Format: Article
Language:English
Subjects:
Anticonvulsants - blood
Anticonvulsants - pharmacokinetics
Anticonvulsants. Antiepileptics. Antiparkinson agents
Biological and medical sciences
Brain Injuries - metabolism
Child
Child, Preschool
Female
Humans
Male
Medical sciences
Neuropharmacology
Oxidation-Reduction - drug effects
Pharmacology. Drug treatments
Phenytoin - blood
Phenytoin - pharmacokinetics
Protein Binding - drug effects
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Summary: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 (r2 = 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 (Vmaxbaseline = 2.82 ± 2.35 mg/kg/day) was observed initially following injury. This was followed by induction of metabolism as reflected by a Vmaxinduced 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.
ISSN:0091-2700
1552-4604
DOI:10.1177/009127000004001216