Pharmacokinetics of 619C89, a novel neuronal sodium channel inhibitor, in acute stroke patients after loading and discrete maintenance infusions.

Abstract

1. This was a multi-centre, placebo controlled, randomized, dose-escalating design study in which five dosing regimens of 619C89/placebo were evaluated in 48 stroke patients. Loading infusions of 0.5, 1, 1.5, 2 and 2.5 mg kg-1 over 1 h were followed by respective maintenance infusions of 0.25, 0.5, 0.75, 1 and 1.25 mg kg-1 over 30 min at 8 hourly intervals for 3 days. 2. Plasma concentrations of 619C89 and its N-oxide, 341C90, and N-demethylated, 78C90, metabolites were assayed using an LC-MS-MS method. Plasma concentration-time profiles after the final maintenance infusion were subjected to conventional noncompartmental pharmacokinetic analysis. 3. For 619C89, geometric CL means ranged between 0.71 and 0.99 1 h-1 kg-1 for maintenance infusions up to 1.25 mg kg-1 over 30 min, with an overall mean of 0.85 l h-1 kg-1 (95% CI: 0.70-1.04 l h-1 kg-1). Geometric Vss means ranged between 13.2 and 27.9 l kg-1 for the same doses, with an overall mean of 22.5 l kg-1 (95% CI: 16.4-30.9 l kg-1). The ANOVA results revealed that neither CL, Vss nor t1/2 were significantly different across the five dosing regimens (P values: 0.82, 0.54 and 0.61, respectively). 4. Average AUC for 341C90 was 270% and that for 78C90 was 62% of the AUC for 619C89. The AUCm/AUCp-ratios were similar at all dose levels for each metabolite. Values of t 1/2 for 341C90 were similar to those of 619C89 whereas t1/2 for 78C90 was about three-fold longer than that of parent drug. 5. In conclusion, the pharmacokinetics of 619C89 are independent of dose in acute stroke patients. The pharmacokinetics of 341C90 are probably formation rate-limited and those of 78C90 are elimination rate-limited and are also dose-independent.

• Authors: Z Hussein, I J Fraser, K R Lees, K W Muir, M W Lunnon, S F Hobbiger, J Posner
• Journal: British journal of clinical pharmacology (Br J Clin Pharmacol) Vol. 41 Issue 6 Pg. 505-11 (Jun 1996) ISSN: 0306-5251 [Print] England
• PMID: 8799514 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Randomized Controlled Trial)

Chemical References

• Neuroprotective Agents
• Piperazines
• Pyrimidines
• Sodium Channel Blockers
• sipatrigine

Topics

• Aged
• Cerebrovascular Disorders (blood, drug therapy, metabolism)
• Double-Blind Method
• Female
• Gas Chromatography-Mass Spectrometry
• Humans
• Infusions, Intravenous
• Male
• Middle Aged
• Neurons (drug effects, metabolism)
• Neuroprotective Agents (administration & dosage, blood, pharmacokinetics)
• Piperazines (administration & dosage, blood, pharmacokinetics)
• Pyrimidines (administration & dosage, blood, pharmacokinetics)
• Sodium Channel Blockers