In adults following acute, severe neurotrauma the metabolism of DPH is increased and albumin concentrations decrease. We evaluated 10 prepubescent children (3-11 yrs) who had severe, acute closed head injury (GCS 3-6) to determine the PK of IV DPH. Patients received a loading dose (17.7 ± 3.3 mg/kg) followed by a maintenance dose of 6.8 ± 1.6 mg/kg/day. DPH serum concentration-time data were collected up to 10 days following injury. DPH and albumin concentrations were determined by FPIA and RID, respectively. The Michaelis-Menten (MM) PK model and a time-variant MM model were fit to the total and unbound DPH concentration-time data (ADAPT II™). Unbound concentration-time data were the most reliable since albumin decreased over time (p<0.001). Also, the unbound fraction of DPH was inversely correlated with albumin concentration (r=0.578, p<0.001). The DPH PK parameters (mean ± sd) are summarized as follows:Table V, volume; Km, MM constant; Kind, rate constant of induction; Vmax, maximal velocity †Time variant MM model[Vmax=Vmaxinitial + Vmaxinduced (l-e-kind•T) for time-variant MM model] The time-variant MM model provided a superior fit of the data in 8 patients with no difference between models in 2 patients. In view of the Vmax for DPH reported for normal, non-stressed children (ie. 9.5-11 mg/kg/day), our PK data demonstrate that severe, acute neurotrauma markedly alters the metabolism of this drug. Specifically, a previously unrecognized rapid inhibition of metabolism (ie. mean Vmax = 0.11 mg/kg/day) occurs during the first hours post injury. This is followed by an induction of clearance as reflected by a Vmax (20.8 mg/kg/day) which is approximately 2 fold higher than “normal” values by 10 days post injury. These changes in DPH metabolism are associated with neurotrauma, and explain to a great degree, the variable dose requirements for DPH in these patients.

Table 1
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