SCN1A (C>T) rs3812718 Polymorphism and Phenytoin-Induced Adverse Drug Reactions: Genotyping Versus Therapeutic Drug Monitoring in a Prospective Cohort

BACKGROUND: Phenytoin has a narrow therapeutic index, and therapeutic drug monitoring (TDM) is routinely used to guide dosing. The SCN1A (C>T) rs3812718 polymorphism has been proposed as a pharmacogenomic marker of phenytoin response; however, whether genotyping provides additional predictive value once TDM is already available remains unclear. METHODS: A prospective cohort of 168 adult patients with epilepsy receiving phenytoin monotherapy was recruited from the neurology outpatient department of a tertiary care center. Participants were genotyped for SCN1A (C>T) rs3812718 using real-time polymerase chain reaction and followed for 6 months to assess adverse drug reactions (ADRs). Trough plasma phenytoin concentrations were measured and categorized as subtherapeutic, therapeutic, or supratherapeutic. Associations between genotype and ADRs were assessed overall, by TDM category, and using Cochran-Mantel-Haenszel (CMH) analysis stratified by TDM category. RESULTS: ADRs occurred in 155 of 168 participants (92.3%), predominantly involving the central nervous system (85.7%). The mutant genotype (CT/TT) was present in 81.5% of participants. No significant association was observed between SCN1A genotype and overall or system-specific ADRs (dominant model, P = 0.655; codominant model, P = 0.576). Genotype was also not associated with TDM category (dominant model, P = 0.263; codominant model, P = 0.583). CMH analysis stratified by TDM category showed no association (odds ratio, 0.37; 95% confidence interval, 0.05-2.72; P = 0.330). CONCLUSIONS: In this cohort, SCN1A (C>T) rs3812718 genotyping did not provide additional value beyond routine TDM in predicting phenytoin-induced ADRs. Phenytoin therapy may therefore continue to be guided by TDM rather than by routine genotyping for this variant.