POPULATION PHARMACOKINETICS OF PHENYTOIN IN JAPANESE PATIENTS WITH EPILEPSY - ANALYSIS WITH A DOSE-DEPENDENT CLEARANCE MODEL

The population pharmacokinetic parameters of phenytoin were estimated using routine therapeutic drug monitoring data from 116 epileptic pati ents. The 531 serum concentration values at steady-state after repetit ive oral administration were analyzed using a nonlinear mixed effects model (NONMEM) program designed for estimation of population pharmacok inetic parameters, A one-compartment model with dose-dependent clearan ce was used for the pharmacokinetic analysis of phenytoin. The volume of distribution (V) was estimated to be 1.23 l/kg in a typical 42-kg p atient, assuming that the bioavailability of orally administered pheny toin is 100%. The maximal elimination rate (V-max) and the Michaelis-M enten constant (K-m) were 9.80 mg/d/kg and 9.19 mu g/ml, respectively. The parameter of power function of weight to adjust V and V-max was e stimated to be 0.463. In addition, K-m for phenytoin appeared to be 16 % increased in patients receiving zonisamide concurrently, The populat ion pharmacokinetic parameters of phenytoin will be useful for designi ng dosage regimens in epileptic patients.