Phenytoin dosage requirements and pharmacokinetic variables

The relationships between phenytoin dose, pharmacokinetic variables, patient data, and serum phenytoin concentrations were studied. One hundred sixty-eight adult epileptic patients who were receiving phenytoin were randomly selected and studied retrospectively. The method of Ludden et al. or a Bayesian forecasting technique was employed to estimate the patients' pharmacokinetic values for maximum rate of drug metabolism (Vmax) and the Michaelis-Menten constant (Km). Resulting steady-state serum concentrations were estimated. The daily doses of phenytoin necessary to produce steady-state serum phenytoin concentrations of 10 and 20 micrograms/ml were also determined in patients whose values were definable. Analysis of variance was used to test possible correlations between patient demographic data, pharmacokinetic values, and doses. The majority of patients (85.6%) failed to achieve concentrations between 10 and 20 micrograms/ml when receiving phenytoin sodium 300 mg daily. Patients receiving more than one phenytoin dosage regimen had significant but weak correlations between Vmax and Km. The data suggest that low Km and Vmax values occur concurrently. Initial phenytoin dose based on patients' weights or body surface areas may be useful in determining initial dosage requirements, but estimated pharmacokinetic values for Vmax and Km provide the best guide for dosage adjustment.