Initial Human Experience with Ganaxolone, a Neuroactive Steroid with Antiepileptic Activity
| Autor: | Linyee Shum, Edward P. Monaghan, Donald W. Ashbrook, David A. Lee, Laura A. Navalta |
|---|---|
| Rok vydání: | 1997 |
| Předmět: |
Adult
Male medicine.medical_specialty Ganaxolone Neuroactive steroid Cmax Administration Oral Pregnanolone Pharmacology Drug Administration Schedule Intestinal absorption Excipients Placebos Double-Blind Method Receptors GABA Pharmacokinetics Internal medicine medicine Humans Adverse effect Dose-Response Relationship Drug business.industry Area under the curve Endocrinology Intestinal Absorption Neurology Tolerability Area Under Curve Anticonvulsants Female Neurology (clinical) business medicine.drug |
| Zdroj: | Epilepsia. 38:1026-1031 |
| ISSN: | 1528-1167 0013-9580 |
| DOI: | 10.1111/j.1528-1157.1997.tb01486.x |
| Popis: | 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 gamma-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 (< or =1,500 mg) and after multiple doses (< or =300 mg b.i.d. for 10 days). Steady-state plasma levels (trough) occurred after approximately 7 days of dosing, with mean steady-state plasma concentrations (Cmax) in multiple dose studies of between 32 ng/ml (50-mg doses) and 376 ng/ml (500-mg doses). No serious or life-threatening 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 Cmax values with increasing dose within the expected therapeutic dose range. Safety and tolerability in the clinical program were unremarkable. |
| Databáze: | OpenAIRE |
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