Estimation of Phenytoin Pharmacokinetic Parameters in Epileptic Saudi Patients

Abstract

Objective: The objective of this study is to determine the population pharmacokinetics of phenytoin in Saudi patients and to identify factors that explain variability. Method: A retrospective chart review was performed at King Saud University Medical City on patients who received oral and IV phenytoin. The population pharmacokinetic models were developed using Monolix 4.4. After development of the base model, we investigated several covariates including: age, gender, weight, and total daily dose, and liver functions tests. Results: The analysis included a total of 81 phenytoin plasma concentrations from 43 patients (70% male). Patients’ mean (±SD) age was 41 ± 18.7 years and body weight was 65.4 ± 17.7. The patients received a phenytoin total daily dose (TDD) of 330.5 ± 104.5mg/day, which resulted in trough concentration of 11.2 ± 10.3 mg/L. The data were sufficiently described by one compartment model with linear absorption and non-linear elimination processes. Average parameter estimates for phenytoin V, Vmax, and Km were 0.61 L/h/kg, 6.12 mg/kg/day, and 5.33 mg/L, respectively. The most significant covariates on phenytoin Vmax, and Km were patients’ age, body weight, and cotherapy with valproic acid. Conclusion: The population pharmacokinetic model of phenytoin in Saudi patients was established and significant covariates on the phenytoin model was recognized. This model showed the significant inter-individual variability between subjects. In addition, our findings showed that patients’ age, body weight, and cotherapy with VPA are the most significant covariates on phenytoin Vmax, and Km parameters. Further studies are required to understand the factors that may influence the pharmacokinetics of phenytoin and may assist in drug dosage decisions.