Population pharmacokinetics of phenytoin in mexican adult patients

Abstract

Statement of Purpose, Innovation or Hypothesis: Many factors have been reported that contribute to the wide inter-patient variability of Phenytoin (Phe) disposition: polymorphisms in CYP2C9 and CYP2C19 genes, the body mass weight and the use of polytherapy. The purpose of this study was to develop a population pharmacokinetic model and to determine the covariates affecting the pharmacokinetics (PK) of Phe in Mexican adult patients. Description of Methods and Materials: It was performed a population PK analysis that included 100 steady-state concentrations and associated dosage rates (mg/day) from 50 patients who were in treatment with oral Phe. The PK parameters (Vd, Vm, Km) were estimated by the non-linear mixed effect model using MONOLIX v4.2.0 a computer program designed for population pharmacokinetic analysis. It combines the SAEM (Stochastic Approximation Expectation/ Maximization) algorithm, with a MCMC (Markov Chain Monte Carlo) procedure for maximum likelihood estimation in nonlinear mixedeffects models. We also illustrate how to use MONOLIX to build the covariate model using the Bayesian Information Criterion. The zeroorder absorption rate in a one-compartment model, with Michaelis Menten elimination kinetics, and an exponential error model were used to describe the concentration-time profile of Phe. Data and Results: The maximum elimination rate (Vmax) was estimated to be 11.2 mg/kg/day, The Michaelis-Menten constant (Km) value was 0.327 mg/L. The volume of distribution (Vd) was 70.6 L. The interindividual variability of Vmax, Km, and Vd was estimated to be 0.00253%, 0.00574% and 0.0012% respectively. The Vd was significantly reduced in patients with polytherapy (p < 0.01). Interpretation, Conclusion or Significance: The population pharmacokinetic parameters of phenytoin will be useful for designing dosage regimens in Mexican epileptic patients, whit the purpose of implementing personalized pharmacotherapy