Abstracts

Rationale:
NBI-921352 (also known as XEN901) is a potent and highly selective NaV1.6 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.
Method:
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 3-period (Days 1-4, Days 4-7, Days 7-9) and 3-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 (Tmax), maximum concentration (Cmax), area under the curve from time zero to last time point (AUC0-t) and from time zero to infinity (AUCinf), and terminal elimination half-life (T1/2).
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 Tmax of ~1 hour. Plasma Cmax, AUC0-t, and AUCinf 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 T1/2 of 8.5 hours for both formulations. For the pediatric granules, Tmax was delayed by ~2 hours and Cmax was decreased by ~38% in the fed versus fasted state; AUC0-t and AUCinf were comparable between fed and fasted states. T1/2­ for the pediatric granule was 6 hours in the fed state and 8 hours in the fasted state.
Conclusion:
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:
:N/A