Authors :
Presenting Author: Michelle Guignet, PhD – School of Pharmacy, University of Washington, Seattle, WA, USA
Jonathan Vuong, B.S. – Research Scientist, Center for Epilepsy Drug Discovery, Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA, USA; Ticha Ballapinan, B.S. – Research Scientist, Center for Epilepsy Drug Discovery, Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA, USA; H. Steve White, BPharm, PhD – Professor, Center for Epilepsy Drug Discovery, Department of Pharmacy, School of Pharmacy, University of Washington, Seattle, WA, USA
Rationale:
One-third of people living with epilepsy (PWE) do not respond to their antiseizure medicine (ASM) therapy, putting them at greater risk for higher disease burden, lower quality of life and SUDEP compared to those individuals whose seizures are well controlled. The best predictor of drug resistant epilepsy (DRE) is often a person’s response to their first ASM. However, little is known about whether certain ASM’s or mechanistic classes will prevent the development of pharmacoresistance altogether. Ethical concerns make this impossible to study in randomized controlled clinical trials. However, we utilized an innovative medication-in-food approach to simulate a clinical trial in a rat model of acquired epilepsy to test the HYPOTHESIS that intervention with an effective ASM will prevent the development of pharmacoresistance following status epilepticus induced DRE.
Methods:
We initialized a triple crossover study design with three clinically available ASM’s in adult male Sprague Dawley rats following kainic acid induced status epilepticus (Fig 1). Rats with confirmed epilepsy (i.e., spontaneous recurring seizures) were acclimated to a medication-in-food delivery system with placebo chow for two weeks before enrolling into three monotherapy arms (two weeks each) with carbamazepine (CBZ, 75-150 mg/kg, q.i.d., p.o.), lamotrigine (LTG, 7.5 – 15 mg/kg, q.i.d., p.o.), or levetiracetam (LEV, 100 – 200 mg/kg, q.i.d., p.o.). At the end of each two week treatment arm rats were titrated to the next ASM over the course of 3-5 days. At the end of the study, rats received all three monotherapies but in a different order for a total of three treatment groups: 1) CBZ – LTG – LEV; 2) LTG – LEV – CBZ; 3) LEV – CBZ – LTG. Changes in seizure frequency and severity were recorded via 24/7 videoECoG recording.
Results:
No treatment group resulted in significantly fewer animals with pharmacoresistant seizures at the end of the study. While LTG significantly aggravated seizures in most rats (median increase in seizure frequency: 100%), LEV improved seizure control (median decrease in seizure frequency: 50%; seizure freedom: 1 rat) regardless of treatment order. CBZ, however, demonstrated differential efficacy depending on whether it was administered before LTG (median decrease: 75%, seizure freedom: 2 rats) or after LTG (median: 0%, seizure freedom: 0 rats). Fifty percent of rats (n=16) that did not respond to their first ASM developed subsequent DRE; however, this was not associated with a specific initial ASM therapy.
Conclusions:
These data suggest that the best predictor of DRE was the response to the first ASM. However, no single ASM was identified as a better initial therapy over others. Importantly, we identified that cross tolerance may develop to drugs within a similar mechanistic class suggesting that ASM’s may display differential efficacy based on when they are administered, highlighting that certain drugs may be more effective as a first-line therapy rather than second- or third-line therapy.
Funding:
Work was supported by Department of Pharmacy (UW). MG was supported by American Epilepsy Society Postdoctoral Fellowship.