Population Pharmacokinetics of Phenytoin in Japanese Patients with Epilepsy : Analysis with a Dose-Dependent Clearance Model

Abstract

The population pharmacokinetic parameters of phenytoin were estimated using routine therapeutic drug monitoring data from 116 epileptic patients. The 531 serum concentration values at steady-state after repetitive oral administration were analyzed using a nonlinear mixed effects model (NONMEM) program designed for estimation of population pharmacokinetic parameters. A one-compartment model with dose-dependent clearance was used for the pharmacokinetic analysis of phenytoin. The volume of distribution (V) was estimated to be 1.23l/kg in a typical 42-kg patient, assuming that the bioavailability of orally administered phenytoin is 100%. The maximal elimination rate (V_max) and the Michaelis-Menten constant (K_m) were 9.80mg/d/kg and 9.19μg/ml, respectively. The parameter of power function of weight to adjust V and V_max was estimated to be 0.463. In addition, K_m for phenytoin appeared to be 16% increased in patients receiving zonisamide concurrently. The population pharmacokinetic parameters of phenytoin will be useful for designing dosage regimens in epileptic patients.