Network-based approaches in drug discovery comprise both development of novel drugs interacting with multiple targets and repositioning of drugs with known targets to form novel drug combinations that interact with cellular or molecular networks whose function is disturbed in a disease. Epilepsy is a complex network phenomenon that, as yet, cannot be prevented or cured. We recently proposed multitargeted, network-based approaches to prevent epileptogenesis by combinations of clinically available drugs chosen to impact diverse epileptogenic processes. In order to test this strategy preclinically, we developed a multiphase sequential study design for evaluating such drug combinations in rodents, derived from human clinical drug development phases. Because pharmacokinetics of such drugs are known, only the tolerability of novel drug combinations needs to be evaluated in Phase I in öhealthy" controls. In Phase IIa, tolerability is assessed following an epileptogenic brain insult, followed by antiepileptogenic efficacy testing in Phase IIb. Here, we report Phase I and Phase IIa evaluation of 7 new drug combinations in mice, using 10 drugs (levetiracetam, topiramate, gabapentin, deferoxamine, fingolimod, ceftriaxone, α-tocopherol, melatonin, celecoxib, atorvastatin) with diverse mechanisms thought to be important in epileptogenesis. Six of the 7 drug combinations were well tolerated in mice during prolonged treatment at the selected doses in both controls and during the latent phase following status epilepticus induced by intrahippocampal kainate. However, none of the combinations prevented hippocampal damage in response to kainate, most likely because treatment started only 16-18 h after kainate. This suggests that antiepileptogenic or disease-modifying treatment may need to start earlier after the brain insult. The present data provide a rich collection of tolerable, network-based combinatorial therapies as a basis for antiepileptogenic or disease-modifying efficacy testing.