Non-Steady State Population Kinetics of Intravenous Phenytoin

Abstract

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.

A Mechanism-Based Integrated Pharmacokinetic Enzyme Model Describing the Time Course and Magnitude of Phenobarbital-Mediated Enzyme Induction in the Rat

“…(8) and (9) for all enzymes except 7!-OHT. The same K m,Ind value was used for all induction processes, which is a reasonable modeling assumption, as enzyme induction is the result of PB binding the same nuclear receptor.…”

“…PB exposure increased the production rate (Rin) of all of these induced enzymes according to Eq. (8). The turnover rate kout was estimated to be 0.355 days j1 , corresponding to a half-life of 2 days, for these functional markers.…”

“…(7), and nonlinear models Eqs. (8) and (9). In addition, the presence of a lag time for the induction was assessed:…”

“…The amount of PB in the central compartment influenced the enzyme activity through a nonlinear relation Eqs. (8) and (9) for all enzymes except 7!-OHT, where a step function was used instead Eq. (6).…”

“…There are also examples of step models where full induction occurs in the presence of the inducer and no induction in absence of it, as in the phenytoin autoinduction model (8).…”