Population Pharmacokinetics of Phenytoin in Thai Epileptic Patients

The study determined the population estimates for Km and Vmax of phenytoin in Thai patients. The serum phenytoin concentrations collected prospectively from outpatients who received phenytoin were analyzed to estimate population pharmacokinetic parameters. There were 197 steady-state concentrations and associated dosage rates (mg/day) from 167 outpatients. The data were analyzed using NONMEM, a computer program designed for population pharmacokinetic analysis that allows pooling of data from many individuals. The maximum elimination rate (Vmax) was estimated to be 690 mg/d, based on the assumption that the bioavailability of orally-administered phenytoin was 100%. The Michaelis-Menten constant (Km) value was 16.10 mg/L. The volume of distribution (Vd) was estimated to be 81.90 L. The interindividual variability of Vmax, Km, and Vd was estimated to be 87.46%, 0.15% and 23.96% respectively. The intraindividual (residual) random variability of serum phenytoin concentration was 27.55%. It appears as a linear function of weight on Km (0.265*Wt). Vmax was significantly reduced in patients who consumed alcohol (p<0.01). Vmax of patients who did not consume alcohol was 649 mg/d (SD=135) while Vmax of patients who consumed alcohol was 260 mg/d (SD=63.8). Km was significantly increased in patients who consumed alcohol (p<0.01). Km of patients who did not consume alcohol was 16.1 mg/L (SD=3.49) whereas Km of patients who consumed alcohol was 23.6 mg/L (SD=5.89). The population pharmacokinetic parameters of phenytoin for Thai epileptic patients were different and higher than the parameters obtained in previous studies. The population pharmacokinetic parameters of phenytoin will be useful for designing dosage regimens in Thai epileptic patients. The dosage regimens for patients who consume alcohol should be initiated at lower dose than the standard dose and gradually increased to the maintenance dose.