Abstracts

Rationale: Ganaxolone (GNX), a synthetic analog of the endogenous GABA modulator allopregnanolone, is a first-in-class neurosteroid in development for treatment of epilepsy and other neurological and psychiatric conditions. An intravenous (IV) formulation of GNX was developed and tested in three Good Laboratory Practice (GLP) non-clinical toxicity studies to support IV GNX clinical development to complement existing formulations and expand treatment options for patients who are unable to take oral GNX due to injury, surgery, or illness.Methods: The studies were: 1) Evaluation of toxicity and toxicokinetics of GNX in a 14 day study, in which GNX was administered via an IV bolus dose followed by continuous IV infusion to male and female Sprague-Dawley rats. Reversibility of any effects was assessed after a 1-week recovery. Rats were given control article or GNX at doses of 18, 30 and 42 mg/kg/day for males and 12, 24 and 30 mg/kg/day for females. Vehicle was 30% (w/v) cyclodextrin (Captisol®) in Sterile Water for Injection, USP. Assessment of toxicity was based on clinical observations, body weight, food consumption, sedation observation scores, and clinical and anatomic pathology. Blood samples were collected for toxicokinetic evaluations. 2) A local tolerance study was conducted in female Hra:(NZW)SPF rabbits to evaluate the local irritation potential of GNX when administered as a single 1 mg/kg IV injection or 0.25 mg/dose perivenous (PV) injection in vehicle diluted with sterile saline. In addition to irritation scoring and anatomic pathology, general toxicity was assessed. 3) The hemolytic potential and plasma compatibility of GNX at concentrations up to 1 mg/mL or vehicle was assessed in human whole blood and plasma.Results: IV administration of GNX, in rats, as a bolus IV dose followed by 14 days of continuous IV infusion was well tolerated at all dose levels tested. During the dosing phase, administration of GNX resulted in non-adverse increases in body weight parameters and food consumption, and in clinical signs/sedation observation scores consistent with an anticipated pharmacologic response. No GNX-related changes were noted in clinical pathology parameters or histopathology examination. The doses of 42 mg/kg/day for males and 30 mg/kg/day for females were considered as the No-Observable-Adverse-Effect-Levels (NOAELs), which were correlated to mean AUC0-24 values of 10600 and 9820 ng·h/mL for male and female rats, respectively. There was no evidence of local irritation in rabbits when GNX was given IV or PV. GNX did not cause hemolysis and was compatible with human plasma in vitro.Conclusions: IV GNX did not cause hemolysis and was compatible with human plasma in vitro and was well tolerated when given IV to rats for up to 14 days duration and when given once IV or PV to rabbits. These results support continued clinical development of IV GNX as a potential treatment option for epilepsy and other diseases.