Abstracts

Rationale: AED-effect on photosensitivity is predictive of AED efficacy observed in conventional Phase-III trials (Kasteleijn, Epilepsy Research 2007; Kasteleijn, Neurology 2007).Chronic dosing with VPA(outpatients)abolishes the photosensitive response in >50% of patients with photosensitive epilepsy(Jeavons, Dev Med Child Neurol 1977;Jeavons,Epilepsia 1986;Covanis,Epilepsia 1982). Acute dosing with VPA has displayed in some patients both a full response(Rowan,1978,Adv in Epileptology,p255-60, but also a minimal response in photosensitivity(Abou-Khalil, Epilepsia 2008). We hypothesize that the pharmacodynamic effect of VPA(perhaps certain AEDs in development)may require both a threshold plasma concentration and time to exhibit optimal effect in photosensitivity. Methods: We used data from a previously conducted prospective, placebo-controlled, non-randomized single-blind study. Patients,18-65 y/o were screened for photosensitivity (Kasteleijn,Epilepsia 1999);hourly photic stimulations x12h,using 20 stimulation frequencies & 3 eye conditions (active eye closure, eyes closed, eyes open).Each patient received iv NaVPA;an adaptive dose design(stat VPA levels q3h)permitted dosing flexibility to 1st achieve total VPA ~30 mg/L,increasing 6-7 mg/L/h to 100 mg/L x 11h more.The effect of VPA on PPR was assessed by change in the PPR frequency range (blinded investigator). Results: 13 patients entered the study;12(4 without AEDs)were evaluable.EEG findings:2 showed abolition of photosensitivity(1 exclusively with eyes open,the other with eyes closed and open),8 had a diminished photosensitivity range;2 showed no change.VPA only attenuated the photoparoxysmal response within the 12h time frame of 1st iv NaVPA bolus and continuously ascending infusion,with maximal effect at 5-6 hrs into the infusion.Total VPA concentrations ranged from 27 - 115 mg/L;free levels from 2 -15 mg/L.The suppression in photo-paroxysmal response appeared at VPA > 50 mg/L.Mixed model-linear correlation analysis showed a significant reduction in photosensitivity parameters(high threshold & standard photosensitive response [SPR] units)with increasing total plasma VPA concentration(Table).This effect of acute iv NaVPA,targeting 100 mg/L at 12h,was less than expected when compared to a prior chronic outpatient study with oral VPA therapy achieving similar plasma VPA concentrations. Conclusions: VPA effect on photosensitive response is likely both concentration and time dependent.This has implications for utility of the photosensitivity model in AED drug development. We recommend each new AED being evaluated with the photosensitivity model incorporate the potential influence of time on photosensitive response(plus appropriate dose-ranging).This may help avoid a Type 2 error(not finding significance when there is),and reaching an inappropriate “No-go” decision in terms of AED development. Study sponsored by Abbott & EU Marie Curie Grant FP6 Visual Sensitivity 024224.