ABSTRACT Prevention of epilepsy is a major unmet need in neurology. Approximately 20% of all epilepsy is due to acute brain insult such as traumatic brain injury (TBI, 5%), stroke (10%), and CNS infection (~5%).Following these injuries, there is a latency of days to years before epilepsy develops. This offers opportunity to intervene with treatment to prevent or modify epilepsy. No such treatment exists. Epilepsy is a complex network phenomenon. Epileptogenesis after acute CNS injury involves different pathophysiological processes. We have previously proposed that rational combinations of drugs that engage different targets of the epileptogenic network may be a more effective preventive treatment strategy than treatment with single specific drugs. We recently tested the network approach in rodent models of epilepsy after status epilepticus (SE) by rationally combining a variety of clinically approved drugs that target epileptogenesis by various mechanisms, including anti-inflammatory, anti-oxidant, neuroprotective, and neurotransmitter- modulating effects. Positive outcome from those studies provides the basis for the present proposal to develop epilepsy prevention therapy based on network pharmacology and the repurposing of FDA approved drugs. We shall (1) Compare pharmacokinetics, tolerability and efficacy of treatment with two drug combinations of FDA approved drugs (PrevEp001 and PrevEp002) with good safety profile and different antiepileptogenic effects (triple combinations) in prevention and/or amelioration of PTE in in a validated TBI model of PTE, the rat fluid percussion model (2) Develop novel i.v. formulation(s) of the triple combination and establish a GMP manufacturing process to enable clinical trial supply. (3) Evaluate tolerance and toxicity of the i.v. triple combination formulation treatment in rats by conducting a GLP compliant multiple dose toxicity study. (4) Conduct a pre-IND meeting with the FDA using data obtained from the present project and from our previous SE epileptogenesis studies to allow human phase I-IIa development programs. Overall, the project will provide the basis for conducting the first in human PoC study with the triple combination.