Population pharmacokinetics of phenytoin from routine clinical data in Japan: an update

Abstract

Routine clinical pharmacokinetic data collected from outpatients receiving phenytoin (PHT) were reanalyzed to estimate population pharmacokinetic parameters. There were 756 steady-state PHT concentrations and associated dosage rates (mg/d) from 334 outpatients. The data were analysed using nonlinear mixed effects model (NONMEM), a computer program designed for population pharmacokinetic analysis that allows pooling of data from many individuals. The influence of weight, co-anticonvulsants on the maximum elimination rate (Vm) and age, co-anticonvulsants on the Michaelis-Menten constant (Km) and the influence of dosage form on the bioavailability (F) of PHT were investigated. The Vm and Km of a 60 kg adult outpatient treated with PHT alone were estimated to be 325 mg/d and 2.41 micrograms/ml, respectively, while for a same size individual taking PHT with co-anticonvulsants respective estimates were 351 mg/d and 3.18 micrograms/ml. The parameter of a power function of weight was estimated to adjust Vm for body size. The best function adjusts Vm in proportion to weight to the 0.737 power. The Km for patients less than 15 years old was 24.8% less than that of adults. Assuming the F of PHT to be 1 in patients prescribed a tablet, the F value in patients prescribed a powder was [1-exp(-9.92/Dij)]; Dij is the daily dose of PHT for the ith Cpss in the jth patients (mg/kg/d).