(301) Pharmacokinetics, Food Effect, and Relative Bioavailability of Two Formulations of NBI-921352/XEN901 (Novel Nav1.6-Selective Sodium Channel Blocker) in Healthy Adults: Pediatric Granules and Adult Tablets

Rationale: NBI-921352 (also known as XEN901) is a potent and highly selective Na_V1.6 inhibitor intended for clinical development for the treatment of SCN8A developmental and epileptic encephalopathy (SCN8A-DEE) and other forms of epilepsy. A pediatric-appropriate formulation of NBI-921352 was developed to enable a study in SCN8A-DEE patients. The current study was conducted to assess the pharmacokinetics (PK) of the NBI-921352 pediatric formulation (granules), the impact of food on this formulation, and its relative bioavailability to an adult immediate-release (IR) tablet formulation.

Methods: In this single center, open-label, randomized study, subjects received an adult IR tablet in a fasted state or the pediatric granule formulation of NBI-921352 (50 mg) in fasted and fed (high-fat meal) states. The study implemented a three-period (Days 1-4, Days 4-7, Days 7-9) and three-sequence crossover design. Blood samples were obtained pre-dose and up to 48 hours post-dose for determination of plasma NBI-921352 concentrations using a validated method. PK parameters included time to maximum plasma concentration (T_max), maximum concentration (C_max), area under the curve from time zero to last time point (AUC_0-t) and from time zero to infinity (AUC_inf), and terminal elimination half-life (T_1/2).

Results: Of the 24 enrolled subjects, 16 (66.7%) were male and 15 (62.5%) were white; mean age was 37.0 years. Following the single-dose administration in the fasted state (adult IR tablet or pediatric granule formulation), NBI-921352 was rapidly absorbed with a median T_max of ~1 hour. Plasma C_max, AUC_0-t, and AUC_inf were comparable between formulations. The geometric mean ratio and 90% confidence intervals for these parameters were within the bioequivalence range of 80‐125%. Following absorption, NBI-921352 plasma concentrations declined in a mono-exponential manner with a T_1/2 of 8.5 hours for both formulations. For the pediatric granules, T_max was delayed by ~2 hours and C_max was decreased by ~38% in the fed versus fasted state; AUC_0-t and AUC_inf were comparable between fed and fasted states. T_1/2­ for the pediatric granule was 6 hours in the fed state and 8 hours in the fasted state.

Conclusions: A pediatric granule formulation of NBI-921352 was bioequivalent to the adult IR tablet after single-dose administration in the fasted state. Administration of the pediatric formulation in the fed state (with high-fat meal) delayed the rate, but not the extent, of NBI-921352 absorption, when compared to fasted state. The favorable PK profile of the pediatric granules (e.g., IR characteristics, bioequivalence to the adult IR tablet; no significant food effect on total systemic exposure) makes this formulation suitable for further clinical development of NBI-921352 in pediatric patients with SCN8A-DEE.

Funding: Please list any funding that was received in support of this abstract.: N/A