Intravenously Administered Ganaxolone Blocks Diazepam-Resistant Lithium-Pilocarpine-Induced Status Epilepticus in Rats: Comparison with Allopregnanolone

J Pharmacol Exp Ther. 2019 Mar;368(3):326-337. doi: 10.1124/jpet.118.252155. Epub 2018 Dec 14.

Abstract

Ganaxolone (GNX) is the 3β-methylated synthetic analog of the naturally occurring neurosteroid, allopregnanolone (ALLO). GNX is effective in a broad range of epilepsy and behavioral animal models and is currently in clinical trials designed to assess its anticonvulsant and antidepressant activities. The current studies were designed to broaden the anticonvulsant profile of GNX by evaluating its potential anticonvulsant activities following i.v. administration in treatment-resistant models of status epilepticus (SE), to establish a pharmacokinetic (PK)/pharmacodynamic (PD) relationship, and to compare its PK and anticonvulsant activities to ALLO. In PK studies, GNX had higher exposure levels, a longer half-life, slower clearance, and higher brain penetrance than ALLO. Both GNX and ALLO produced a sedating response as characterized by loss of righting reflex, but neither compound produced a full anesthetic response as animals still responded to painful stimuli. Consistent with their respective PK properties, the sedative effect of GNX was longer than that of ALLO. Unlike other nonanesthetizing anticonvulsant agents indicated for SE, both GNX and ALLO produced anticonvulsant activity in models of pharmacoresistant SE with administration delay times of up to 1 hour after seizure onset. Again, consistent with their respective PK properties, GNX produced a significantly longer anticonvulsant response. These studies show that GNX exhibited improved pharmacological characteristics versus other agents used as treatments for SE and position GNX as a uniquely acting treatment of this indication.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Administration, Intravenous
  • Anesthetics / administration & dosage
  • Animals
  • Anticonvulsants / therapeutic use
  • Diazepam / therapeutic use*
  • Drug Resistant Epilepsy / chemically induced
  • Drug Resistant Epilepsy / drug therapy
  • Drug Resistant Epilepsy / physiopathology
  • Electroencephalography / drug effects
  • Electroencephalography / methods
  • Lithium / toxicity*
  • Male
  • Muscarinic Agonists / toxicity
  • Pilocarpine / toxicity*
  • Pregnanolone / administration & dosage*
  • Pregnanolone / analogs & derivatives*
  • Rats
  • Rats, Sprague-Dawley
  • Status Epilepticus / chemically induced
  • Status Epilepticus / drug therapy*
  • Status Epilepticus / physiopathology

Substances

  • Anesthetics
  • Anticonvulsants
  • Muscarinic Agonists
  • Pilocarpine
  • ganaxolone
  • Lithium
  • Pregnanolone
  • Diazepam