Thesis (M.Sc.In Pharm)--Chulalongkorn University, 2007

Objective: The pharmacokinetic parameters of phenytoin, V[subscript max] and K[subscript m], are necessary for phenytoin maintenance dosage design. Many factors had influenced on these parameters. In addition, these parameters are claimed to be race dependent. Systematic study for these parameters in Thai epileptic patients are lacked especially in children. Therefore, this study was designed to determine pharmacokinetic parameters of phenytoin in Thai epileptic children and to study the factors which influence these two pharmacokinetic parameters of phenytoin Method: The study was conducted in patients who attended at neurology clinic of children at Chonburi Hospital during October 2007 to March 2008. Total 39 patients participated throughout the study. All included patients were under 15 years old and received phenytoin monotherapy for epilepsy. There were 39 steady-state serum concentrations which collected prospectively from these 39 out-patients. Data was analysed using Nonlinear Mixed Effect Model (NONMEM), a computer program designed for pharmacokinetic analysis. Results: For determination of pharmacokinetic parameters, a data set of steady-state serum concentrations were analysed using NONMEM. The estimated pharmacokinetic parameters of phenytoin in Thai epileptic children were V[subscript max], K[subscript m] and Vd equaled to 5.16 mg/kg/d, 4.50 µg/mL and 0.31 L/Kg, respectively. The interindividual random variabilities of V[subscript max], K[subscript m] and Vd were 94.33%, 5.55% and 29.86%, respectively. According to the results of exploring covariates, the influence of covariates including age, weight and gender were studied. It was found that age and gender were not significantly correlated with V[subscript max] and Vd while patient’s body weight was statistically significant correlated with V[subscript max] (r=0.358, p = 0.025). For developing the model, body weight was added into the base model of V[subscript max]. The decrease of objective function value between base model and covariate model of V[subscript max] did not decreased by significantly (p<0.05). Therefore, the model that was selected and used to evaluate pharmacokinetic parameters was the base model. Conclusion: The obtained V[subscript max] and K[subscript m] values in this study may be very useful for designing more accurate and appropriate dosage regimens for the treatment of Thai epileptic children. However pharmacokinetic parameters of phenytoin in this study may have limitations, the further studies should be performed in future.