Abstract Details

Title Characterization of a Novel Repeat-dosing Model for Preclinical Diazepam Studies

Topic General Neurology

Presentation(s) P1 - Poster Session 1 (8:00 AM-9:00 AM)

Poster/Presentation
Number 4-001

Objective To identify a suitable diazepam (DZP) dosing strategy in rats for subsequent subchronic in vivo efficacy studies.

Background DZP elimination pharmacokinetics are substantially faster in rats than humans, complicating subchronic and chronic studies in rats. Previous rat studies suggest that repeat doses of intraperitoneal (IP) DZP 20 mg/kg result in sustained DZP accumulation in serum and cerebrospinal fluid but impair neurologic function, measured by righting reflex.

Design/Methods Adult male Sprague Dawley rats (~400 g) were administered 3 repeat doses of IP DZP (0.75, 1.5, 3, or 6 mg/kg) 1 hour apart. A separate group received only a single 3-mg/kg dose. Righting reflex was evaluated. Blood was collected at 10 minutes and 1, 3, and 6 hours after the final injection. Brain samples were collected at 1, 3, or 6 hours. Dose-dependent changes in plasma and brain DZP concentrations were evaluated.

Results Repeat dosing of DZP (0.75–3 mg/kg) resulted in a dose-dependent increase in plasma and brain DZP levels up to 6 hours. A single 6-mg/kg dose resulted in substantial impairment of righting reflex and was not studied further. Brain-to-plasma ratios suggest a modest accumulation of DZP in the brain as long as 6 hours (3 mg/kg: 38.3±34.6 ng/g vs 23.8±18.4 ng/mL). Brain accumulation of DZP at 6 hours was greater after repeat doses vs a single dose (repeat: 38.2±34.6 ng/g vs single: 6.1±3.4 ng/g).

Conclusions In this rat model, a repeat-dosing paradigm of DZP ≤3 mg/kg resulted in sustained DZP levels in plasma and brain. Accumulation of DZP in rat brain vs plasma suggests that DZP may be long-acting at the site of action. This repeat-dosing paradigm for DZP in rats mimics plasma drug concentrations seen in humans, offering a preclinical tool to study the impact of benzodiazepine rescue therapy on seizure-cluster biology.

Authors/Disclosures
Emily Rogers, PhD (Neurelis) PRESENTER	Dr. Rogers has received personal compensation for serving as an employee of Neurelis.
Michelle Guignet (University of Washington)	No disclosure on file
Evelyn K. Shih, MD, PhD (Neurelis, Inc.)	Dr. Shih has received personal compensation for serving as an employee of Neurelis, Inc. Dr. Shih has received personal compensation for serving as an employee of SK Life Science, Inc.
Enrique Carrazana (Neurelis, Inc.)	Enrique Carrazana has received personal compensation for serving as an employee of Neurelis. Enrique Carrazana has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for Hawaii-Biotech, CND Life Sciences, Apex Labs. Enrique Carrazana has stock in Neurelis, CND, Apex.
Adrian L. Rabinowicz, MD, FAAN (Neurelis, Inc.; Center for Molecular Biology and Biotechnology, Charles E. Schmidt College of Science, Florida Atlantic University)	Dr. Rabinowicz has received personal compensation for serving as an employee of Neurelis, Inc. Dr. Rabinowicz has stock in Neurelis, Inc.

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