Non-steady state population kinetics of intravenous phenytoin.
This observational study explored the effects of demographics, sickness, and polypharmacy on the non-steady state population pharmacokinetics of intravenous phenytoin. One hundred fifteen patients were studied. Models were developed using the NONMEM program with hybrid first-order conditional estimation. A Michaelis-Menten model with delayed induction was preferred over a Michaelis-Menten model without induction, a Michaelis-Menten model with immediate induction, or a linear model with delayed induction. When the data were fit to a Michaelis-Menten model with delayed induction, the volume of distribution (Vd) was found to depend on weight and serum albumin. The Vd was estimated to be 0.95 l/kg, assuming an albumin level of 3 g/dl. The Michaelis-Menten constant (km) was estimated to be 7.9 mg/l. The baseline maximum metabolic rate was 580 mg/day for a 70-kg patient. The average time to onset of induction was 59.5 hours. If a fever developed after induction began, it increased the extent of induction. This model was evaluated retrospectively in 26 additional patients, yielding a mean prediction error of -0.4 mg/l (-3.0-2.2 mg/l) and a mean absolute prediction error of 4.7 mg/l (3.2-6.2 mg/l) based on two-level feedback. Given the large interindividual variances in maximum metabolic rate, phenytoin levels should be measured frequently.
Department of Pharmaceutical Services, Metropolitan Hospital, Grand Rapids, Michigan 49506, USA.
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D000368:Aged; D000927:Anticonvulsants / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007275:Injections, Intravenous; D008432:Mathematical Computing; D008875:Middle Aged; D008954:Models, Biological; D015233:Models, Statistical; D010672:Phenytoin / Q000008:administration & dosage / Q000493:pharmacokinetics*; D012189:Retrospective Studies
D000927:Anticonvulsants; D010672:Phenytoin