Authors :
Presenting Author: Julia Tsai, Ph.D – Ovid Therapeutics
Jay Mukherjee, PhD – Ovid Therapeutics
John Williamson, - – University of Virginia
Tae Hyun Kim, PhD – Ovid Therapeutics
Suzie Ferreira, PhD – Ovid Therapeutics
Zhong Zhong, PhD – Ovid Therapeutics
Manoj Malhotra, MD – Ovid Therapeutics
Jaideep Kapur, MBBS, PhD – University of Virginia
Patrick Sarmiere, PhD – Ovid Therapeutics
Rationale: GABA-amino transferase (GABA-AT) is the enzyme that catabolizes GABA, the primary inhibitory neurotransmitter in the adult CNS. OV329 is a highly potent GABA-AT inhibitor and has the potential to be a next-generation antiseizure drug. By inhibiting GABA-AT activity, OV329 elevates GABA levels, thereby enhancing inhibitory neurotransmission to reduce neuronal hyperexcitability and terminate epileptiform activities associated with treatment-resistant seizures, e.g. Status Epilepticus (SE). Results from in vivo efficacy studies have shown that acute administration of OV329 can be effective in suppressing both chronic seizures (e.g. mouse intra-hippocampal kainate model of mesial temporal lobe epilepsy) and acute seizures (e.g. rat intravenous (IV)-pentylenetetrazol model of generalized seizures).
To be effective in SE, the onset of action of OV329 should be relatively rapid and IV route of administration of OV329 is a potentially viable option. Therefore, it is critical to understand the pharmacokinetic (PK) profile of OV329 after IV administration and its relationship with the pharmacodynamic (PD) effect such as the extent of GABA-AT inhibition and change in GABA level within the brain. We assessed the PK parameters of OV329 in plasma and brain at multiple doses following IV administration and examined the corresponding PD effect by measuring GABA-AT activity and GABA level in brain tissue. Additionally, we examined the efficacy of OV329 in the rat lithium-pilocarpine model of SE after IV administration.Methods: OV329 (1,3,10 mg/kg) was administered IV to C57BL/6 mice and tissue samples were collected at multiple time points up to 24 hrs. Brain GABA concentration and exposure of OV329 was determined by LC-MS/MS, and PK parameters were determined. Using a biochemical assay, GABA-AT activity was measured in the brain tissue homogenates. To test the efficacy in the rat lithium-pilocarpine model of SE, OV329 was administered IV after SE induction and the duration of SE was determined from EEG.
Results:
A single, acute IV (bolus) dose of 10 mg/kg OV329 led to a significant reduction (~30%) of GABA-AT activity in the brain within an hour and persisted for 24 hrs following dosing. Moreover, the GABA concentration in brain homogenate was gradual, but significantly increased by 1hr with a peak around 4 hrs (~50%) and stayed elevated for at least up to 8 hrs. Mass spectrometric analysis demonstrated a significant and dose-dependent exposure of OV329 in plasma as well as in the brain within a few minutes after IV administration. Consistent with the PD effect, OV329 significantly reduced the duration of SE in rats induced by lithium-pilocarpine.
Conclusions: Collectively, these data demonstrate that IV administration of OV329 resulted in higher exposure of OV329 in the brain with decreased GABA-AT activity which resulted in elevated levels of GABA in the brain. Finally, the IV administration of OV329 suppressed the duration of SE in the rat pilocarpine model of SE.
Funding: Ovid Therapeutics Inc.