Abstracts

RATIONALE: Approximately one third of women with intractable epilepsy have seizures that are influenced by the menstrual cycle. Catamenial seizures most commonly increase during the perimenstrual phase. Because seizure exacerbations correlate with the decrease in endogenous progesterone levels, studies have looked at using progesterone to treat these seizures. Evidence suggests that progesterone therapy can eliminate the increase in seizure frequency. Ganaxolone has demonstrated anticonvulsant activity in a presurgical trial design. Therefore, this neuroactive, synthetic analog of a naturally occurring metabolite of progesterone, allopregnanolone, may prove particularly effective against catamenial seizures. This open-label pilot study assessed the safety, tolerability, pharmacokinetics, and anticonvulsant activity of ganaxolone in two women with catamenial epilepsy.
METHODS: Patients with catamenial epilepsy received ganaxolone 300 mg PO BID in this phase II trial. The treatment period began on day 21 of their menstrual cycle and continued through the third full day following the beginning of menstruation. The duration of this pulse dosing treatment was four months. Inclusion criteria were: 1) to have at least two complex partial seizures, with or without secondary generalization, per month with at least twice the average daily seizure frequency during the perimenstrual period [within 3 days before or after onset of menses] compared with the average daily seizure frequency during the follicular [days 4 to 9 following onset of menses] and luteal [4-12 days prior to onset of menses] phases of the cycle, 2) to have menstrual cycles over the past 4 months with a duration of 26 to 32 days, and 3) have had no seizure-free perimenstrual periods over the past 6 months.
RESULTS: Two women, ages 32 and 40 years, were recruited. Both were incompletely maintained on the combination of valproic acid and phenytoin. At the end of the first month, both patients reported a lessened total seizure burden with a complete absence of perimenstrual seizure activity. A trend of lessened perimenstrual and non-perimenstrual seizure activity compared to baseline continued throughout the remaining 3 months. Beyond initial somnolence, neither patient reported adverse effects. Laboratory profiles and antiepileptic drug concentrations were not affected by ganaxolone.
CONCLUSIONS: Both patients had a moderate improvement in their catamenial seizures from ganaxolone. The side effects were mild. A longer study with more patients is needed to verify these promising, yet preliminary results.
Support: CoCensys & NIH General Clinical Research Center Grant [pound]M01RR00034