To develop oral formulations of ezogabine and XEN901 suitable for administration to pediatric patients ≥1 month of age.

The neuronal KCNQ (Kv7.2/7.3) potassium channel opener ezogabine (retigabine) was previously marketed as a tablet formulation (Potiga^®/Trobalt^TM, GlaxoSmithKline) for adjunctive treatment of focal onset seizures in adults.  While this formulation was used off-label in the pediatric population, no pediatric formulation was developed.  Both ezogabine (XEN496) and XEN901 are being developed by Xenon as precision medicine treatments of pediatric KCNQ2 developmental and epileptic encephalopathy (KCNQ2-DEE) and SCN8A developmental and epileptic encephalopathy (SCN8A-DEE), respectively.  To support these development programs, convenient pediatric-friendly oral immediate-release formulations were required for flexible weight-based dosing without requiring extemporaneous compounding.

Critical formulation attributes were optimized through an iterative series of design cycles combined with in vitro and animal pharmacokinetic (PK) testing.  Excipient compatibility testing was performed, followed by dissolution assessments of ungranulated mixtures.  Following granulation, particle size distribution, palatability, release profile, stability and non-specific binding to glass and common plastics were evaluated for candidate formulations.  Lead formulations were evaluated in animal PK studies.

Both pediatric formulations were chemically stable, palatable, scalable, and compatible with common food vehicles and feeding apparatus (e.g., nasogastric feeding tubes, baby bottles) without significant non-specific binding.  Both exhibited immediate-release dissolution profiles and their biopharmaceutical performance was confirmed in vivo.  The pediatric formulation of XEN901 exhibited suitable PK properties in a dog PK study and XEN496 resembled compounded Potiga^® in a cross-over rat PK study. Packaging strategies suitable for both program development phases were identified and implemented.

Pediatric formulations of ezogabine (XEN496) and of XEN901 were developed as granules suitable for dispersal in breast milk, infant formula or soft foods, packaged in single-use sachets or sprinkle capsules of varying fill weights and progressed into Phase 1 PK studies in healthy adult subjects.