Abstracts

SPM 927 (formerly harkoseride) was previously reported to reduce seizure frequency in a phase 2, multicenter, open-label trial in subjects with uncontrolled partial seizures taking one (25%) or two (75%) concomitant AEDs (Study SP607). We report the steady-state plasma concentrations of concomitant AEDs during Study SP607 to determine whether efficacy was due to elevations of these levels.
The trial consisted of a 4-week baseline, a maximum 8-week titration, and a 4-week maintenance period. SPM 927 started at 100mg/day (50mg BID) and increased weekly by 100mg/day until either 600mg/day or the maximum tolerated dose (MTD) was reached. Concomitant AED doses were constant throughout. To determine baseline steady state values, AED levels were obtained at Visit 1 and 30 min prior to the first dose of SPM 927 at Visit 2. To determine whether SPM 927 influenced these levels, samples were again obtained at Cmax for SPM 927 (~2-4 hours post-dose) at the end of the titration phase and at the end of the maintenance phase. Mean steady state plasma levels were calculated for each concomitant AED. Plasma levels were measured by validated analytical methods using appropriate ranges of calibration. Samples were analyzed only for subjects with at least one pre-treatment and two post-treatment samples. Differences between pre-treatment and post-treatment AED levels were analyzed using ANOVA.
At least one dose of SPM 927 was taken by 91 subjects. A 50% or greater reduction in seizure frequency occurred in 33% and 7 subjects were seizure-free throughout the maintenance period, as reported previously. The median MTD for SPM 927 was 300mg/day; ~ 50% of subjects had an MTD of 400-600mg/day. Mean ([plusmn] SD) baseline AED plasma levels were: carbamazepine (9.6mg/ml [plusmn] 2.9mg/ml), carbamazepine-10,11-epoxide (2.1mg/ml [plusmn] 0.8mg/ml), gabapentin (15.6mg/ml [plusmn] 14.4mg/ml), lamotrigine (7.5mg/ml [plusmn] 5.6mg/ml), levetiracetam (34.1mg/ml [plusmn] 30.6mg/ml), monohydroxy derivative of oxcarbazepine (26.6mg/ml [plusmn] 12.0 mg/ml), phenytoin (14.2mg/ml [plusmn] 6.5mg/ml), and zonisamide (23.6mg/ml [plusmn] 11.8mg/ml). ANOVA did not reveal any differences between plasma concentrations at Visit 1 and plasma concentrations at the end of titration and the end of maintenance (p[gt]0.05).
Plasma concentrations of concomitant AEDs remained stable during adjunctive treatment with SPM 927, suggesting that the observed seizure reduction in this trial is not the result of elevations of concomitant AED levels. However, these results require confirmation from an ongoing placebo-controlled trial with larger numbers of subjects.
[Supported by: Schwarz Biosciences]