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 rt ere altered in prepubescent pediatric patients within the fi rst 10 days following severe, acute traumatic brain injury. Patients (n = 1 0) received phenytoin loading doses (15-20 mg/kg) follow ed by a maintenanc e regimen (7 mg/kg/day) initiated within 12 hours of the loading dose. Phen ytoin 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-Men ten pharmacokinetic models were fit to the unbound phenytoin concentration- time data (ADAPT II(TM)). Albumin concentrations significantly decreased ov er 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 t h e data in 7 patients with no difference between models in 3 pa tien ts. R apid inhibition of metabolism (Vmax(baseline) = 2.82 +/- 2.35 mg/kg/day) wa s observed initially following injury. This was followed by induction of me tabolism as reflected by a Vmax(induced) of 20.79 +/- 13.71 mg/kg/day, whic h was approximately twofold higher than reported values for nonstressed chi ldren. Children with severe, acute neurotrauma were found to have markedly altered protein binding and phenytoin metabolism. (C)2000 the American Coll ege of Clinical Pharmacology.