Precision management of cenobamate in drug-resistant epilepsy: integrating pharmacogenetics, therapeutic drug monitoring, and real-world clinical strategies.

Cenobamate (CNB) demonstrates high efficacy in drug-resistant focal epilepsy, yet optimal management requires personalized strategies. This exploratory case series describes five patients selected from a cohort of 125 individuals treated with CNB, examining the relationship between pharmacogenetic (PGx) profiles and clinical outcomes. Clinical data and therapeutic drug monitoring (TDM) were integrated with targeted Next-Generation Sequencing of key metabolic genes (UGT2B7, UGT2B4, CYP2E1, CYP2B6, CYP2A6, CYP3A4, CYP2C19) to predict metabolizer phenotypes. Three patients (Cases 1, 3, 4) achieved seizure freedom or ≥50% response at sub-target or target doses (100-200 mg/day) enabling early de-escalation of concomitant sodium channel blockers and valproate. This success was supported by a proactive digital communication protocol and a mandatory 100 mg clinical checkpoint. Case 2-a non-responder at 400 mg/day despite therapeutic plasma levels (28.22 mg/L)-exhibited a predicted "Ultrarapid Metabolizer" (UM) phenotype characterized by UGT2B7 Haplotype 4 and CYP2E1 duplication, suggesting possible pharmacokinetic contribution to non-response. Case 5 experienced dose-limiting toxicity at 100 mg/day; we hypothesized this toxicity could be driven by a drug-drug-gene interaction involving CNB-mediated CYP2C19 inhibition that impairs clearance of N-desmethylclobazam (the active metabolite of clobazam) in a patient with impaired CYP2A6 activity and intermediate UGT2B7 function. As an exploratory case series, these findings require validation in adequately powered prospective studies. Associations between UM phenotype and non-response, and between PM phenotype and dose-limiting toxicity, represent preliminary observations that may reflect pharmacokinetic variability. Nevertheless, our experience is consistent with a personalized, sub-target dose titration strategy that may help minimize adverse events in complex polypharmacy settings.