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Initial Human Experience with Ganaxolone, a Neuroactive Steroid with Antiepileptic Activity
Author(s) -
Monaghan Edward P.,
Navalta Laura A.,
Shum Linyee,
Ashbrook Donald W.,
Lee David A.
Publication year - 1997
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/j.1528-1157.1997.tb01486.x
Subject(s) - tolerability , pharmacokinetics , medicine , neuroactive steroid , cmax , pharmacology , adverse effect , dosing , methohexital , allopregnanolone , clobazam , anesthesia , epilepsy , gabaa receptor , propofol , receptor , psychiatry
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.