Abstracts

Rationale:
NBI-921352 (also known as XEN901) is a potent and highly selective Nav1.6 inhibitor intended for the treatment of SCN8A developmental and epileptic encephalopathy (SCN8A-DEE) and other forms of epilepsy. In early clinical development, NBI-921352 will be used as adjunctive therapy with other antiepileptic drugs, many of which are potent cytochrome P450 (CYP) inducers. Phenytoin, a strong inducer of CYP3A4 and a moderate inducer of CYP1A2 and CYP2C19, is a commonly administered anti-seizure medication and is recognized as a reference P450 inducer by the US Food and Drug Administration. Therefore, it was selected for the current study, which evaluates the impact of phenytoin CYP induction on the pharmacokinetics (PK) of NBI-921352.
Method:
In this single-center, open-label, randomized study, healthy subjects received a single 100 mg oral dose of NBI-921352, after an overnight fast, on Day 1 and Day 12. Phenytoin 100 mg was administered three times a day on Day 3 through to the morning of Day 12. Blood samples were obtained pre-dose and up to 48 hours post-dose for determination of plasma NBI-921352 concentrations using a validated bioanalytical method. PK parameters included maximum concentration (Cmax), area under the curve from time zero to infinity (AUCinf), time to maximum plasma concentration (Tmax), and terminal elimination half-life (T1/2). Phenytoin PK samples were collected prior to morning dose on Day 3 and Days 7-12 to evaluate trough concentrations. Safety evaluations included adverse event (AE) monitoring.
Results:
Of the 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 NBI-921352 Cmax­ with phenytoin compared to its administration alone was 122% (91%-162%). However, the GMR (90% CI) for NBI-921352 AUCinf was 93% (82%-105%), indicating that phenytoin administration did not affect total systemic exposure of NBI-921352. Median T­max of NBI-921352 was ~1 hour, with or without phenytoin, and 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 majority of AEs were mild, and the most common treatment-related AEs were dizziness, headache, and nausea.
Conclusion:
In this study in healthy adults, no change was observed in the total systemic exposure of NBI-921352 after 10 days of administration of phenytoin, indicating no meaningful drug-drug interaction between NBI-921352 and phenytoin was observed. In addition, no apparent impact on safety was observed when NBI-921352 was co-administered with phenytoin. These data suggest that no dose adjustment will be required if NBI-921352 is co-administered with phenytoin or other strong inducers of CYP3A4 and/or moderate inducers of CYP1A2 and CYP2C19.
Funding:
:N/A