Utilization of Quantitative EEG Spectral Analysis to Characterize IV Ganaxolone PK/PD Properties in Refractory Status Epilepticus (RSE)
Abstract number :
2.1
Submission category :
4. Clinical Epilepsy / 4C. Clinical Treatments
Year :
2021
Submission ID :
1826221
Source :
www.aesnet.org
Presentation date :
12/5/2021 12:00:00 PM
Published date :
Nov 22, 2021, 06:53 AM
Authors :
Henrikas Vaitkevicius, MD - Marinus Pharmaceuticals; Eva Rybak - Marinus Pharmaceuticals; Maxim Meersman - Epilog, Gent, Belgium; Pieter Van Mierlo - Epilog, Gent, Belgium; Joseph Hulihan - Marinus Pharmaceuticals; Maciej Gasior - Marinus Pharmaceuticals
Rationale: Ganaxolone, a synthetic neuroactive steroid, binds to synaptic and extrasynaptic GABAA receptors at a site distinct from benzodiazepines and barbiturates to enhance GABAergic inhibitory tone. Ganaxolone is in clinical development for status epilepticus and rare pediatric epilepsies. It has complex pharmacokinetic properties with a large volume of distribution, extensive brain exposure, and produces rapid and profound background EEG changes. This analysis evaluated CNS-specific pharmacokinetic and pharmacodynamic properties of intravenous (IV) ganaxolone using spectral analysis of EEG during a Phase 2 study in refractory status epilepticus (RSE) (NCT03350035).
Methods: We analyzed data from continuous EEG recording in 17 patients with RSE enrolled in the phase 2 study. The alpha/delta ratio and suppression ratio (SR) were computed from 30 min before (baseline) through 48 hours after initiation of IV ganaxolone. The percentage change relative to baseline was calculated. Bivariate correlations of alpha/delta power and SR with observed and predicted serum ganaxolone levels were performed.
Results: A substantial increase in the alpha/delta ratio was observed immediately after the start of IV ganaxolone in 76% (13/17) patients. The median time-to-peak and corresponding median percentage increase in the alpha/delta ratio were 5 min and 93% respectively, matching the observed median time to SE cessation. For the SR, an increase was observed in 53% (9/17) patients, with a median time-to-peak of 6.5 min and median percentage increase of 55%. A significant positive linear correlation was found between the SR and the initial serum ganaxolone levels post-IP initiation (R2=0.86, p=0.0016).
Conclusions: This analysis of PK/PD characteristics of IV ganaxolone shows changes in quantitative EEG measures which correlate with initial serum ganaxolone levels and SE cessation in patients with RSE.
Funding: Please list any funding that was received in support of this abstract.: This work was sponsored by Marinus Pharmaceuticals.
Clinical Epilepsy