Abstracts

Rationale: Ganaxolone (GNX), a synthetic allopregnanolone analog, is in development for treatment of epilepsy. Quantitative electroencephalography (qEEG) is underexplored as a pharmacodynamic (PD) measure for CNS therapeutics. The objective of this study was to develop a population pharmacokinetic (PK) - PD model of GNX IV administered to healthy participants. Methods: Using data from a completed phase 1 clinical trial in 36 healthy volunteers, a population PK/PD model was developed sequentially using nonlinear mixed effects modeling (NONMEM V7.2) to quantitatively characterize the exposure-response relationship for the qEEG parameter alpha-power after GNX administration. Two, three, and four-compartment linear mammillary models were explored. Effect compartment and indirect effect models were tested in the PD analysis for alpha-power. Demographics were evaluated as potential covariates. The adequacy of the model was assessed with standard model diagnostic methods. Results: Ganaxolone PK was best described by a 3-compartment model with linear elimination. Alpha-power after GNX administration was best characterized by an effect compartment model, due to the difference in timing between the administration of the drug and the onset of a resulting pharmacodynamic effect which could be related to CNS diffusion, target binding, or delay between target engagement and down-stream signaling. BMI was identified as a significant covariate on clearance. The maximum increase in alpha-power from baseline in the average patient was approximately 75.3%. The GNX concentration that produces 50% of the maximum effect (EC50) was 52.2 ng/mL. The Hill coefficient was estimated to be 1.28. Conclusions: GNX affected qEEG in a predictable and dose-responsive manner. The EC50 was 52.2 ng/mL, a concentration which was achieved through IV administration. Future studies could determine whether reduced spike frequencies and increases in alpha power are associated with successful seizure treatment with GNX. Funding: Marinus Pharmaceuticals provided funding for this work.