A randomised controlled trial to evaluate the use of genotyping and therapeutic drug monitoring versus only therapeutic drug monitoring as a strategy for risk minimisation in patients of epilepsy on phenytoin therapy

Objectives: Phenytoin has a unique feature of accumulating in the body due to its non-linear elimination kinetics. Being a drug with a narrow therapeutic index, phenytoin needs routine therapeutic drug monitoring (TDM) to adjust the dose. Polymorphisms in cytochrome P450 (CYP [2C9 and C19]) genes reduce drug metabolism, increase drug concentrations and thus produce adverse drug reactions (ADRs). Detection of polymorphisms helps to predict the susceptibility to toxicity. Hence, this study was designed to compare the addition of genotyping to TDM of phenytoin as an investigational tool for assessing plasma levels and occurrence of ADRs in epileptic patients on phenytoin therapy as a part of risk minimisation. Materials and Methods: This randomised controlled trial was prospective and double-blind. Epileptic patients were randomised into two groups. One group received therapeutic doses of phenytoin based on their CYP2C9 and CYP2C19 genotyping, followed by monitoring drug levels by TDM. The other group was treated with phenytoin based on the clinician’s judgement. Monitoring of blood levels was done by TDM. Chi-squared test was used to analyse the difference in the occurrence of ADRs between the two groups. Results: In each group, Group A (genotyping and TDM) and Group B (TDM alone), 30 patients were enrolled, totalling 60 patients. Baseline characteristics of participants with or without CYP2C9 and CYP2C19 expression were statistically not significant. At the 6-month follow-up visit, in both CYP2C9 and CYP2C19 groups, the plasma concentration of phenytoin was statistically significant. We found 10 ADRs, and between the two groups, the difference in the occurrence of ADRs was non-significant. Conclusion: We found no significant utility of the addition of the genotyping in risk minimisation of phenytoin when used with TDM. Genotyping can be considered at the time of initiation of phenytoin therapy in epileptic patients.