Estimation of population pharmacokinetic parameters of free-phenytoin in adult epileptic patients

Background. Serum concentrations of free-phenytoin (F-PHT) obtained in adult epileptic patients receiving PHT in monotherapy were analyzed to estimate the Michaelis-Menten pharmacokinetic parameters. Methods. Steady-state F-PHT serum concentrations, PHT dosing history, and associated information were collected prospectively. The maximum metabolic rate (Vm) and Michaelis-Menten constant (Km) of F-PHT and their interindividual variability data were estimated using nonlinear mixed effects modeling (NONMEM). Results. Twenty-nine patients with two or more available steady-state F-PHT serum concentrations (total of 63 dose/serum concentration pairs) met the inclusion criteria. Patients were taking PHT (100-500 mg/day) in monotherapy. The population estimates of F-PHT for Vm and Km were 9.1 mg/kg/day and 7.3 mg/L, respectively. The model was prospectively evaluated in a small group (seven) of additional patients. Conclusions. The recommended daily dose in this population to achieve a F-PHT concentration of 1.5 mg/L is 6.1 mg/kg. (c) 2005 IMSS. Published by Elsevier.