Abstracts

This abstract is a recipient of the Grass Young Investigator Award

Rationale: Clinical response to conventional antiseizure medications (ASMs) and available treatment options for patients with Dravet Syndrome (DS) have been sub-optimal. Therefore, there is an ongoing unmet need to discover novel treatments for seizure control in DS. The recommended standard of care for DS includes either valproic acid (VPA) or clobazam (CLB) as first-line options. Combining CLB and VPA is recommended if treatment with these ASMs alone does not provide seizure control. Most pediatric DS patients use a second-line drug adjunctively with VPA and CLB. Stiripentol (STP) and, more recently, cannabidiol (CBD) are considered the best second-line agents. Additionally, selecting doses in polytherapy rely on the clinician's experience. Previous studies in our lab demonstrated that STP and CBD alone were not effective against hyperthermia-induced seizures in our mouse model of DS, suggesting that this model is an excellent drug-resistant model. To set the stage for investigational compound screening and pharmacokinetic studies using a polytherapy approach that is commonly used in the clinic, we used the second-line DS therapies of either STP or CBD treatment as an add-on approach to the combination of CLB and VPA treatment in a preclinical mouse model of DS, a model used in the Epilepsy Therapy Screening Program (ETSP) testing.

Methods: Both female and male heterozygous DS (Scn1a^A1783/WT) experimental mice between P49 and P77 were used. We performed the hyperthermia-induced seizure test in DS mice (n=10) after concurrent pretreatment with varying doses of STP (30 mg/kg, 70 mg/kg, 100 mg/kg and 130 mg/kg; ip) or CBD (70 mg/kg, 100 mg/kg, 135 mg/kg and 150 mg/kg; ip) with CLB (5 mg/kg; ip) and VPA (75 mg/kg; ip). The control group (n=10) was given CLB (5 mg/kg; ip) and VPA (75 mg/kg; ip). All drugs were administered based on their time-to-peak effect. The temperature at which a seizure occurred was recorded and any adverse effects on tolerability were noted (e.g., sedation, ataxia). Seizure protection of the add-on therapy was assessed by comparing the temperature at which seizures occurred to the treatment control group. 

Results: We observed a significant dose-dependent increase in the median temperature at which seizures occurred with either STP or CBD when administered in combination with CLB and VPA and compared to the control group that received only CLB plus VPA. No significant drug adverse effects were observed, except for reduced mobility in STP and hypothermia in CBD-treated mice at all doses.

Conclusions: ETSP testing of investigational compounds as add-on drugs combined with CLB and VPA may be an essential approach to guide dose selection for achieving optimum seizure protection and tolerability. Future work will determine potential pharmacokinetic interactions in triple-drug therapies for DS.

Funding: This project has been funded in part by Federal funds from the National Institute of Neurological Disorders and Stroke, Epilepsy Therapy Screening Program, National Institutes of Health, and Department of Health and Human Services, under Contract No. HHSN271201600048C. It was also partly funded by the University of Utah - College of Pharmacy Skaggs Graduate Research Fellowship.