Relationship Between Phenytoin Response Therapy with Blood Levels and CYP2C9 Polymorphisms in Epilepsy Patients

Sumarno

Phenytoin is the first generation OAE which is still used as the first line to treat seizures and the outcome is inadequate in 30% of epileptic patients with uncontrolled seizures. Phenytoin is an OAE that has nonlinear pharmacokinetic characteristics, a narrow therapeutic index and in several studies has shown variability in plasma drug levels. This shows that the use of phenytoin at the usual dose shows variability in the achievement of plasma phenytoin levels and the response. Phenytoin dose adjustment is complex because it follows a nonlinear (Michaelis-Menten) pharmacokinetics. A slight increase in the dose will cause a disproportionate increase in plasma phenytoin levels. The genetic variability of cytochrome P450 (CYP) CYP2C9 (CYP2C9 polymorphism) affects drug metabolism (90%) and influences plasma phenytoin levels and response to therapy.

The purpose of this study was to analyze the relationship between response to therapy and phenytoin levels and CYP2C9 polymorphisms in epilepsy patients,  This research is a prospective observational study with a cross sectional design Epileptic patients used 80% phenytoin monotherapy, in combination with other 20% OAEs. The therapeutic response achieved was sub-therapeutic 25%, therapeutic 75% and no toxic response was found. There is variability in the achievement of Css min and Css max levels of phenytoin with an average phenytoin dose of 295 ± 7.39 mg/day. In this study, no CYP2C9*2 and CYP2C9*3 polymorphisms (variants) were found, the results of the identification of CYP2C9 research subjects all showed CYP2C9*1 variants (Wild-type/normal). Statistical analysis of the Spearman's rho correlation between the dose of phenytoin (mg/kgBW/day) with Css min and Css max showed the Correlation Coefficient (strength of the relationship) for Css min was -0.270 and Css max was -0.299 (p > 0.05), this was caused by the characteristics the distribution of the data is not normal and the number of samples is relatively small. Monitoring therapy and individualization of phenytoin doses need to be considered because there are variations in response and phenytoin levels even though all patients identified the same CYP2C9*1 variant (Wild-type/normal).

Keywords: Phenytoin, Therapy Response, Plasma Phenytoin Levels, CYP2C9 Polymorphisms