PHARMACOKINETIC-PHARMACODYNAMIC COMPARISON OF GANAXOLONE IN NORMAL RATS AND IN A RAT MODEL OF CATAMENIAL EPILEPSY
Abstract number :
3.082
Submission category :
1. Translational Research
Year :
2008
Submission ID :
8714
Source :
www.aesnet.org
Presentation date :
12/5/2008 12:00:00 AM
Published date :
Dec 4, 2008, 06:00 AM
Authors :
Doodipala Reddy and M. Rogawski
Rationale: Ganaxolone is a synthetic, orally active analog of the neurosteroid allopregnanolone, a potent positive modulator of GABA-A receptors with antiseizure activity. Early stage clinical trials were encouraging and the drug is currently being evaluated in two Phase IIB controlled clinical trials in adult patients with partial-onset seizures and in pediatric patients with infantile spasms. We have developed preclinical evidence supporting the utility of ganaxolone as a treatment for perimenstrual catamenial epilepsy, a menstrual cycle-related seizure disorder characterized by an increase in seizures at the time of menstruation. Specifically, we found that the anticonvulsant activity of ganaxolone is enhanced in the catamenial epilepsy model. In this study, we sought to determine if the enhanced activity is due to pharmacokinetic or pharmacodynamic factors. Methods: In our model of catamenial epilepsy, we induce pseudopregnancy in young rats with gonadotrophins, which results in persistently elevated progesterone and estrogen. Following 12 d of pseudopregnancy to simulate the high hormonal levels in the luteal phase of the human menstrual cycle, the animals are treated with finasteride (100 mg/kg, ip), causing a rapid fall in allopregnanolone as occurs around the time of menstruation. After withdrawal, seizure threshold, as assessed by intravenous infusion of pentylenetetrazol (PTZ), is markedly reduced, indicating greater seizure susceptibility. Brain and plasma ganaxolone levels were determined with a LC-MS method. Results: Control and neurosteroid withdrawn animals received a single s.c. dose of ganaxolone (7 mg/kg), resulting in an elevation in PTZ threshold that peaked at 30 min and returned to baseline at 120-180 min. As expected from previous studies, ganaxolone caused a markedly greater elevation of PTZ threshold in the withdrawn animals than in controls (ratio of AUC seizure threshold increase withdrawn:control = 1.76), indicating a greater sensitivity to the anticonvulsant effects of ganaxolone. Surprisingly, plasma and brain ganaxolone levels were reduced in withdrawn animals (69% of control). Adjusting for the reduced brain levels, the pharmacodynamic sensitivity to ganaxolone was enhanced 2.29-fold in the withdrawn animals compared with controls. There was a significant increase in clearance (CL) of ganaxolone in the withdrawn animals, which accounts for the reduced plasma and brain levels. Brain levels of ganaxolone reached a peak more slowly (Tmax-brain, ~30 min) than in plasma (Tmax-plasma, ~15 min); the Tmax-brain value corresponds with the peak elevation in seizure threshold. Conclusions: These studies confirm the enhanced anticonvulsant activity of ganaxolone in a rat model of catamenial epilepsy. The enhanced activity occurs in the face of decreased plasma and brain ganaxolone levels, indicating a marked increase in pharmacodynamic sensitivity. Our results support a “neurosteroid replacement strategy” with ganaxolone or other GABA-A receptor modulating neurosteroid for the treatment of breakthrough seizures in perimenstrual catamenial epilepsy.
Translational Research