Abstracts

Rationale: Rationale: Vigabatrin (VGB), the only FDA approved GABA-amino transferase (GABA-AT) inhibitor, is widely used to treat infantile spasms and refractory complex partial seizures. However, the peripheral visual field defects (VFD) observed after chronic usage in patients limit the clinical utility of VGB. GABA-AT is the key enzyme that breaks down GABA, the primary inhibitory neurotransmitter in adult CNS. Therefore, the inactivation of GABA-AT can elevate GABA levels and potentially reduce neuronal hyperexcitability associated with seizures. OV329, a highly potent GABA-AT inhibitor, has the potential to be a next-generation antiseizure drug and is currently under development. While the underlying mechanism of the ocular toxicity associated with long-term usage of VGB is still unclear, one prevailing hypothesis is that the (S+)-VGB, the active isomer, preferentially accumulates in retina and may contribute to VFD. Unlike VGB, which is clinically used as a racemic mixture, OV329 is synthesized only as the active (S+) isomer. The present study examines whether OV329 has a similar tendency to accumulate in rodent eyeballs, and more specifically in retina, after continuous infusion for days. The mechanistic insights gained here will potentially inform how OV329 might be different than VGB relative to retinal accumulation.


Methods: Methods: To detect OV329 and VGB in retina, tandem mass spectrometry-based bioanalytical methods (LC-MS/MS) were established. Using subcutaneous (SC) infusion via osmotic pump or intraperitoneal injection, C57BL6 mice were administered OV329 (5mg/kg/day) or VGB (80mg/kg/day), both pharmacologically appropriate dose based on the molecular potency on GABA-AT. Plasma samples were analyzed at different time points during infusion. Brain, retina, eyeball, and blood samples were collected at 48 hours after initiation of SC infusion. Concentrations of OV329 and vigabatrin in plasma, retina, eyeball, and brain tissue after 2-days of continuous SC infusion were compared. PK data were analyzed using the Phoenix Win Nonlin software program.


Results: Results: Plasma exposure at 4, 8, 24, 32 and 48- hours post-initiation of SC infusion demonstrated a steady state plasma level of OV329 (25.7±1.69 ng/ml) and VGB (1462 ±104 ng/ml) within 7 hours. After 2-days of continuous SC infusion, the ratio of VGB concentration in retina to plasma was ~4.3 fold greater, whereas no OV329 was detected either in retina or in eyeball at this timepoint. VGB partitioned into retina (~400%) more efficiently than in brain (~17%). Additionally, acute, IP administration of 5mg/kg OV329 resulted in 80.4±17ng/ml in retina after 30-minutes of dosing.


Conclusions: Conclusions: Collectively, these data suggest that while VGB preferentially accumulates in retina, OV329 does not tend to accumulate either in eyeball or in retina at a dose that is deemed efficacious in rodents and the absence of OV329 in retina is likely not due to the limit of detection. However, it remains to be seen whether preferential retinal accumulation of VGB directly correlates with the adverse ocular effect and warrants further investigation.


Funding: Ovid Therapeutics Inc.