2002
Paris, France
Phenytoin covariate models for Michaelis-Menten pharmacokinetics in adult epileptic patients
D. Santos Buelga1, M.J. García1, MJ Otero2, A. Martin Suarez1, A. Dominguez-Gil2, JC.Lukas1
Phenytoin plasma concentration minima at steady state (Cmin) were monitored in 230 adult outpatients with epilepsy. The drug is metabolized by cytochrome P450 through a saturable process. The population was randomly divided into an index (n = 200; 620 x Cmin) group for model development, and a validation group (n = 30). The Michaelis Menten (MM) kinetics (average of 3 occasions per individual) was modeled with the first order (FO) nonlinear mixed effects method of NONMEM employing the steady state model of the rate of administration versus concentration, to determine the MM parameters. The maximum biotransformation rate (Vmax) was [typical population value (CV%)] 17.9 mg/h (28%) and the concentration at half the saturation rate (Km) was 4.4 mg/L (73%). The demographic covariates weight, age, height, sex as well as comedication with carbamazepine, phenobarbital and valproic acid were tested for their explicatory capacity of the interindividual variabilities. The final model was Vmax = 13.9 + 3.97*WT/67 mg/h (25%) (428 mg/day for the typical patient) and Km = 4.29 mg/L (68%) with a reduction in the log-likelihood objective function of 13.03 (chi-square significant at p<0.001) and a 11% reduction in the determinant of the covariance matrix. This model was validated in the remaining 30 patients (60 x Cmin) with bias (confidence interval) 0.03 (-.07, 0.13) and precision 0.16 (-0.47, 0.79).