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

• Published in: British journal of clinical pharmacology Vol. 41; no. 6; pp. 505 - 511
• Main Authors: HUSSEIN, Z., FRASER, I. J., LEES, K. R., MUIR, K. W., LUNNON, M. W., HOBBIGER, S. F., POSNER, J.
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell Science Ltd 01-06-1996; Blackwell Science
• Subjects: 341C90; 619C89; 78C90; Aged; Biological and medical sciences; Cardiovascular system; Cerebrovascular Disorders - blood; Cerebrovascular Disorders - drug therapy; Cerebrovascular Disorders - metabolism; Double-Blind Method; Female; Gas Chromatography-Mass Spectrometry; Humans; Infusions, Intravenous; Male; Medical sciences; Middle Aged; Neurons - drug effects; Neurons - metabolism; Neuroprotective Agents - administration & dosage; Neuroprotective Agents - blood; Neuroprotective Agents - pharmacokinetics; Original; pharmacokinetics; Pharmacology. Drug treatments; Piperazines - administration & dosage; Piperazines - blood; Piperazines - pharmacokinetics; Pyrimidines - administration & dosage; Pyrimidines - blood; Pyrimidines - pharmacokinetics; Sodium Channel Blockers; stroke; Vasodilator agents. Cerebral vasodilators; Human; Nervous system diseases; Stroke; Intravenous administration; Metabolite; Multicenter study; Cardiovascular disease; Ionic channel; Cerebral disorder; Blood plasma; Vascular disease; Increasing dose; Randomization; Central nervous system disease; Placebo; Sodium ion; Double blind study; Antagonist; Pharmacokinetics; Cerebrovascular disease
• ISSN: 0306-5251; 1365-2125
• DOI: 10.1046/j.1365-2125.1996.03625.x

1This 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.
2Plasma 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.
3For 619C89, geometric CL means ranged between 0.71 and 0.99 l 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).
4Average 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 t1/2 for 341C90 were similar to those of 619C89 whereas t1/2 for 78C90 was about three‐fold longer than that of parent drug.
5In 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.