Abstracts

Rationale: Diazepam is widely used for the management of acute seizures, including seizure clusters and status epilepticus. In the development of new formulations and delivery systems for these applications, information regarding the blood levels required for seizure protection is necessary. Here, we determined the minimal plasma concentration of diazepam at steady state that elevates pentylenetetrazol (PTZ) seizure threshold in rats.  Methods: Diazepam pharmacokinetic parameters were determined following an acute intravenous bolus injection using a non-compartmental pharmacokinetic approach. The derived parameters were used to design two dosing schemes. In the first scheme, diazepam at various doses was continuously infused in freely-moving catherized rats for four half-lives in order to achieve a near steady-state condition. In the second scheme, steady state was achieved rapidly with a loading dose followed by a maintenance infusion for one half-life. In both cases, the intravenous pentylenetetrazol (PTZ) seizure threshold test was administered at the end of infusion period. Results: The pharmacokinetic parameters determined following an acute intravenous bolus injection (80 µg/kg) were Cmax, Vd, Cl, t½α and t½β of 41.3 ± 2.8 ng/ml, 608 ml, 22.1 ml/min, 13.7 ± 2.1 min and 76.8 ± 12.6 min, respectively. Diazepam plasma levels of 77 ng/ml or greater were associated with a robust elevation of seizure threshold in the four half-life infusion scheme studies. In the rapid steady-state experiments, levels of 58 ng/ml or greater were associated with antiseizure effects. Conclusions: Plasma concentrations of approximately 60–80 ng/ml or greater in rats are associated with an antiseizure effect of diazepam. Funding: The work was supported by the Acorda Therapeutics Inc.