Initial Human Experience with Ganaxolone, a Neuroactive Steroid with Antiepileptic Activity

ABSTRACT

Summary: Purpose: Studies were conducted to establish the safety, tolerability, and pharmacokinetics of the antiepileptic drug (AED) ganaxolone. Ganaxolone belongs to a novel class of neuroactive steroids called epalons, which specifically modulate the γ-aminobutyric acid type A (GABA_A) receptor in the central nervous system (CNS). Chemically related to progesterone but devoid of any hormonal activity, the epalons have potent antiepileptic, anxiolytic, sedative, and hypnotic activities in animals.

Methods: Ninety-six healthy male and female volunteers received ganaxolone in a variety of formulations, doses, and dosing regimens. The pharmacokinetics of ganaxolone were systematically characterized, and adverse events associated with drug use were documented.

Results: Ganaxolone was well tolerated after single doses (≥1,500 mg) and after multiple doses (≥300 mg b.i.d for 10 days). Steady-state plasma levels (trough) occurred after ˜7 days of dosing, with mean steady-state plasma concentrations (C_max) in multiple dose studies of between 32 ng/ml (50-mg doses) and 376 ng/ml (500-mg doses). No serious or lifethreatening adverse events attributed to the drug were observed. The majority of adverse events reported were mild (82%) to moderate (14%) and were limited to headache, dizziness, somnolence, gastrointestinal disturbances, and malaise.

Conclusions: Ganaxolone alone or formulated with pharmaceutical-grade excipients is rapidly absorbed from the gastrointestinal tract after oral administration in doses ranging from 50 to 1,500 mg. Pharmacokinetic analysis revealed a linear and proportional increase in the area under the curve (AUC) and C_max values with increasing dose within the expected therapeutic dose range. Safety and tolerability in the clinical program were unremarkable.