Pharmacokinetic Modeling to Predict the Phenytoin Level in Blood by Using STELLATM Program
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Abstract
Phenytoin, has become the drug of choice for partial seizure and generalized tonic – clonic seizure.Due to its narrow therapeutic index, nonlinear pharmacokinetic and considerable therapeutic variation among patients, dose adjustment based on therapeutic drug monitoring (TDM) is required. However, TDM is not feasible for all patients due to its time and cost consuming. Presently, blood level prediction of phenytoin is based on calculation, which might lead to misinterpretations. Therefore, the aims of this study were to develop a pharmacokinetic model using STELLATM software for phenytoin blood level prediction, and to evaluate the validity of the pharmacokinetic modelin comparison to the empirical phenytoin blood level of epileptic patients at Chonprathan Medical Center, Srinakharinwirot University.
The retrospective study was conducted on epileptic patients treated with phenytoin sustained – release capsule. Their phenytoin blood level wasethically collected from medical records of Chonprathan Medical Center, Srinakharinwirot University between February 2015 to February 2016. The one compartment pharmacokinetic model of phenytoin was developed using STELLATM software for the prediction of patient’s maximum initial velocity value (Vmax), The validity of the pharmacokinetic model was evaluated by comparing the results from obit graph using simple linear regression analysis. The estimated phenytoin blood level at doses of 200 and 300 mg based on Vmax and body weight (mean ± SD) were used. Moreover, the effect of valproic acid on Km1 values in patients with co-administration of phenytoin and valproic acid was evaluated. Root mean square error (RMSE) between the result of phenytoin blood levels from TDM and orbit graph and between the result of phenytoin blood levels from TDM and the pharmacokinetic model were 7.65 and 7.77, respectively. The phenytoin blood level predicted by orbit graph was comparable to that from pharmacokinetic model. The ranges of phenytoin blood level at the doses of 200 and 300 mg were 1.53 – 4.947 and 3.00 – 19.450 µg/ml, respectively. Furthermore, it is shown that valproic acid reduced binding affinity between phenytoin and CYP450enzymes as patients taking both phenytoin and valproic acid had greater Km value (7.17 ± 3.64 mg/L) than population pharmacokinetic (Km = 4).
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