3. Pharmacokinetics, Food Effect & Relative Bioavailability of Two Formulations of NBI-921352/XEN901 in Healthy Adults: Pediatric Granules & Adult Tablets

Pharmacokinetics, Food Effect & Relative Bioavailability of Two Formulations of NBI-921352/XEN901 (Novel NaV1.6-Selective Sodium Channel Blocker) in Healthy Adults: Pediatric Granules & Adult Tablets

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. This single-center, randomized, open-label, 3-period, 3-sequence, crossover study was conducted to assess the pharmacokinetics (PK) of a pediatric-appropriate formulation of NBI-921352 (granules), including the impact of food and its bioavailability relative to an adult immediate-release (IR) tablet formulation. Study subjects received an adult IR tablet or the pediatric granule formulation of NBI-921352 (50 mg) in fasted and fed states. Blood samples were obtained pre-dose and up to 48 hours post-dose to determine plasma NBI-921352 concentrations using a validated method. Of 24 enrolled subjects, 16 (66.7%) were male and 15 (62.5%) were white; mean age was 37.0 years. Following single-dose administration of both formulations in the fasted state, NBI-921352 was rapidly absorbed with a median time to maximum plasma concentration (Tmax) of ~1 hour. Maximum plasma concentration (Cmax) and areas under the curve (AUC0-tlast and AUC0-inf) were comparable between formulations. The geometric mean ratios and 90% confidence intervals for these parameters were within the bioequivalence (BE) range of 80‐125%. Terminal elimination half-life (T1/2) of NBI-921352 was 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 states; AUC0-tlast and AUC0-inf were comparable between fed and fasted states. T1/2¬ for the pediatric granule formulation was 6 hours in the fed state and 8 hours in the fasted state. These results indicate that the 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 delayed the rate, but not extent, of NBI-921352 absorption compared to the fasted state. The favorable PK profile of the pediatric granules (e.g., IR characteristics, BE 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. 

  • Gregory Beatch
  • Rostam Namdari
  • Jay A. Cadieux
  • Gordon Loewen
  • Ernesto Aycardi
  • Xenon Pharmaceuticals; Neurocrine Biosciences