NBI-921352 (also known as XEN901), a potent and highly selective Nav1.6 inhibitor, is being evaluated for the treatment of SCN8A developmental and epileptic encephalopathy (SCN8A-DEE) and other forms of epilepsy. In clinical development, NBI-921352 will be used adjunctively with other antiseizure medications (ASMs), many of which are potent cytochrome P450 (CYP) inducers. Phenytoin, a strong CYP3A4 inducer and moderate CYP1A2/CYP2C19 inducer, is a commonly used ASM and recognized by the FDA as an index P450 inducer. Therefore, it was selected for the current study to evaluate the impact of phenytoin CYP induction on the pharmacokinetics (PK) of NBI-921352. In this single-center, open-label, randomized study, healthy subjects received single oral doses of NBI-921352 (100 mg) after overnight fasts on Days 1 and 12. Phenytoin (100 mg 3x daily) was administered on Day 3 through to the morning of Day 12. Blood samples were obtained pre-dose and up to 48 hours post-dose to determine NBI-921352 plasma concentrations using a validated bioanalytical method. Phenytoin PK samples were collected prior to morning doses on Day 3 and Days 7-12 to evaluate trough levels . Safety evaluations included adverse event (AE) monitoring. Of 17 evaluable subjects, 14 (82.4%) were male and 17 (100%) were white; mean age was 41.6 years. The geometric mean ratio (GMR) with 90% confidence interval (CI) for maximum concentration (Cmax¬) of NBI-921352 plus phenytoin versus NBI-921352 alone was 122% (91%-162%). However, the GMR (90% CI) for NBI-921352 area under the curve (AUC0-inf) was 93% (82%-105%), indicating that phenytoin did not affect total systemic NBI-921352 exposure. Median time to maximum plasma concentration (Tmax) of NBI-921352 was ~1 hour, with or without phenytoin. Terminal elimination half-life (T1/2) of NBI-921352 alone (10 hours) was comparable to NBI-921352 with phenytoin (8 hours). Phenytoin trough levels reached apparent steady-state by Day 10. No deaths, serious AEs, or discontinuations due to AEs occurred during the study. The most common treatment-related AEs were dizziness, headache, and nausea, all of which were generally mild. These findings suggest that no dose adjustment will be required for co-administration of NBI-921352 with phenytoin or other strong CYP3A4 inducers and/or moderate CYP1A2/CYP2C19 inducers.