Pharmacokinetic, Pharmacodynamics, and Safety Study of Intravenous Ganaxolone in Healthy Adult Volunteers

Abstract number : 3.165
Submission category : 3. Neurophysiology / 3C. Other Clinical EEG
Year : 2022
Submission ID : 2204638
Source : www.aesnet.org
Presentation date : 12/5/2022 12:00:00 PM
Published date : Nov 22, 2022, 05:26 AM

Authors :
Megan Barra, PharmD – Marinus Pharmaceuticals, Inc.; Maciej Gasior, MD, PhD – Marinus Pharmaceuticals, Inc.; Henrikas Vaitkevicius, MD – Marinus Pharmaceuticals, Inc.; Aatif Husain, MD – Duke University; Shruti Raja, MD – Duke University; David MacLeod, MB BS, FRCA, Dip IMC – Duke University; Jeff Guptill, MD – Duke University; Joseph Hulihan, MD – Marinus Pharmaceuticals, Inc.; Eva Rybak, PharmD – Marinus Pharmaceuticals, Inc.

Rationale: Ganaxolone is a neuroactive steroid anticonvulsant that rapidly alters neuronal excitability by modulating both synaptic and extrasynaptic ɣ-aminobutyric acid (GABAA) receptors. An intravenous (IV) formulation of ganaxolone is currently under investigation for the treatment of refractory status epilepticus. The objective of this study was to assess the pharmacokinetics (PK), pharmacodynamics (PD) and safety of IV ganaxolone.

Methods: This was phase 1 clinical trial of IV ganaxolone in healthy subjects. In Stage 1, subjects received either vehicle control (n=6) or IV ganaxolone administered as a bolus over 5 minutes; 10 mg IV (n=3) and 30 mg IV (n=3), 20mg IV (n=6) bolus over 2 minutes; 30 mg IV (n=6) bolus over 60-minutes; and 10 mg IV (n=6) bolus over 60-minutes. For Stage 2, IV ganaxolone was administered as a 6 mg bolus over 5 minutes followed by a continuous infusion of 20 mg/hour over 4 hours (n=6). Plasma ganaxolone sampling was performed through 48 hours post-administration. PK was evaluated by non-compartmental analysis in Phoenix WinNonLin. Data with adjusted r-square < 0.8 were excluded. Quantitative electroencephalography (qEEG) measures, bispectral index (BIS), modified observers' assessment of alertness and sedation (MOAA/S), plasma concentrations, and safety data were collected.

Results: Thirty-six subjects were enrolled; one subject in Stage 1 withdrew from the study. Other than sex and age (Stage 1: 80% male, mean age 33.5 years; Stage 2: 66.7% female, mean age 30.5 years), there were no notable differences in demographic variables between the two groups. Pharmacokinetic values varied across the cohort groups and correlated with the dose and rate of administration for IV ganaxolone (Table 1). BIS reduction after ganaxolone administration was observed (Figure 1). In Stage 1, after administration of IV bolus over 2-, 5-, and 60-minutes, time to maximal BIS reduction was a median (range) 8 minutes (5, 15), 15 minutes (5, 60), and 65 minutes (30, 120), respectively. In Stage 2, time to maximal BIS reduction was 148-minutes (35, 220). Across all cohorts, deep sedation (defined as an MOAA/S score 0-1), was reported in a single patient 5-minutes post-administration of a 30-mg IV bolus over 5 minutes with return to baseline arousal 15-minutes post-administration. Rapid changes in qEEG parameters were more pronounced after administration of an IV bolus over 2 or 5 minutes. No deaths, severe AEs, or serious AEs (SAEs) were reported.  No cardiovascular or respiratory AEs were reported, and no clinically significant findings were reported for laboratory values, vital signs, ECG data, physical examinations, or C-SSRS.

Conclusions: After administration of IV ganaxolone, a dose and administration-dependent response of pharmacokinetic and pharmacodynamic effects was observed. More pronounced and rapid effects occurred in subjects receiving ganaxolone IV bolus over 2 or 5 minutes. Overall, IV ganaxolone was generally well tolerated at the doses studied.

Funding: This work was sponsored by Marinus Pharmaceuticals, Inc.