Abstracts

Rationale: Ezogabine (EZG) was a first in class Kv7 channel opener approved in June 2011 as adjunctive therapy for partial onset seizures and removed from the market because of its three times a day dosing that did not fit within an adjunctive therapy profile and decreased use as a result of bluish skin discoloration and potential for retinal pigment changes that were not known if reversable at the time of removal from the market in June 2017. The pigmentary changes were associated with dimers of EZG-EZG and its primary N-acetyl metabolite of retigabine NAMR-NAMR (Prescott, AES 2014; Evans, AES 2014).  The cumulative probability of experiencing discoloration of the lip, nail, skin was 16.7% over 5 years and < 2% over 2 years.  The evidence by 2014 was inconclusive that retinal pigmentation changes also impacted visual function.  A prodrug of EZG provides NCE composition of matter under a 505b2 approval pathway, and potentially reduces/eliminates the formation of the dimer that causes discoloration and allow for improved PK by reducing peak to trough swing in exposure by the oral route and support parenteral administration.

Methods: Prodrug XYG-204 was assessed for in vitro plasma stability, rodent PK of prodrug and EZG and pharmacology in the maximal electroshock (MES) assay for anticonvulsant activity.  XYG-204 was also assessed for solution stability against formation of EZG.

Results: XYG-204 is soluble in water and saline at concentrations > 200 mg/mL and stable against forming EZG for > 11 days at room temperature.  It degrades in vitro in mouse plasma within 4 h and rat plasma by 24 h at 37°C.  When administered by the intramuscular (IM) route in solution at a dose of 75 mg/kg (0.5 mL/kg) in male SD rat resulted in 18.7% of maximal protection in the MES assay at 5 minutes post dose IM, 47% protection by 15 minutes, 97.6% by 1 hour and full protection from 2-8 hours before decreasing in effect.  Mean plasma levels for XYG-204 decreased from a mean of 42 µM at 5 minutes through 23 hours to < 1 µM.  While XYG-204 decreased in concentration, EZG increased from a mean of ~700 nM at 5 min to 20 µM by 2 h and remained above 10 µM through 8 h before decreasing to ~ 1 µM at 23.5 h. In CF-1 mice administered EZG or XYG-204 at 100 mg/kg IP 30 minutes before MES were 7/8 protected for EZG with EZG plasma conc of 14 mM and 3/3 protected with XYG-204 with 62 µM EZG; 150 mg/kg XYG-204 was lethal to 5/5 mice with EZG drug levels at 161 µM.

Conclusions: These data support the hypothesis that prodrugs of ezogabine can be designed to release ezogabine by multiple routes of administration and reduce/eliminate formation of the dimers.

Funding: Xyzagen, Inc. provided the funding for this research.