Abstracts

Rationale: Antiepileptic drug (AED) effect on photosensitivity is predictive of efficacy in conventional Phase-III trials (Kasteleijn, Neurology 2007; 69:1027). The efficacy of VPA in photosensitive epilepsy has never been confirmed in a prospective placebo-controlled clinical trial. The purpose of this study was to determine the pharmacodynamic effect on the photoparoxysmal response (PPR) of small changes in VPA concentration, over a range of 30-100 mg/L via constant infusion of intravenous NaVPA. Methods: We conducted a prospective, dual-center, placebo-controlled, non-randomized single-blind study. Patients 18-65 years old were screened for photosensitivity using standardized methodology (Kasteleijn, Epilepsia 40[S4], 1999; 75). For qualifying subjects, the study involved 2 separate sessions of hourly photic stimulations for 12h, using 20 stimulation frequencies and 3 eye conditions (active eye closure, eyes closed, eyes open). Each patient received intravenous saline placebo in session 1 and intravenous NaVPA in session 2, at 5mg/kg initially, then 1.145 mg/kg/hr for 12h thereafter. An adaptive dose design permitted dosing flexibility. Hourly total and free VPA levels were obtained. Stat VPA levels every 3 hours allowed adjustment of the dose in order to approach target levels. The design allowed a slow increase in total plasma VPA concentrations from 0 to ~30 mg/L in 15 min, then by increments of 6.36 mg/L to 100 mg/L over the next 11h, producing VPA exposure (AUC) changes <14% for 8 to 12h. The effect of valproate on the PPR was assessed by change in the PPR frequency range. These evaluations were performed by a blinded investigator. IRB approval was obtained prior to the initiation of this study; written informed consent was obtained from all patients. Results: To date, 11 patients entered the study; 10 are evaluable. Only 3 adverse events were reported -rash in 1 patient who did not finish the study and abdominal symptoms in two patients. No change in lab values, neurological or general physical examination occurred. No generalized tonic clonic seizures occurred throughout the study. EEG findings: 1 showed abolition of photosensitivity, 8 had a diminished photosensitivity range; 1 showed no change. The VPA suppressive effect was greatest in the eyes-open condition in 5, and in the eye closure condition in 3 patients. Total VPA concentrations ranged from 27 - 115 mg/L; free levels from 2 -15 mg/L. IV NaVPA reduced the photosensitivity range over the course of infusion, maximally, 5-6 hrs post-dose. The suppression in photo-paroxysmal response appeared at VPA > 50 mg/L. Conclusions: As expected, IV VPA attenuated or abolished the PPR in patients with photosensitivity, at concentrations >50mg/L. Further analysis is warranted to determine whether VPA effect is merely concentration-dependent or related to the product of concentration x time. Knowledge about VPA pharmacodynamics could be beneficial in optimizing clinical care in epilepsy. Study sponsored by Abbott & EU Marie Curie Grant FP6 Visual Sensitivity 024224.