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Pharmacokinetics of 619C89, a novel neuronal sodium channel inhibitor, in acute stroke patients after loading and discrete maintenance infusions
Author(s) -
HUSSEIN Z.,
FRASER I. J.,
LEES K. R.,
MUIR K. W.,
LUN M. W.,
HOBBIGER S. F.,
POSNER J.
Publication year - 1996
Publication title -
british journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.216
H-Index - 146
eISSN - 1365-2125
pISSN - 0306-5251
DOI - 10.1046/j.1365-2125.1996.03625.x
Subject(s) - pharmacokinetics , dosing , placebo , geometric mean , medicine , analysis of variance , stroke (engine) , pharmacology , anesthesia , zoology , chemistry , mathematics , biology , statistics , alternative medicine , pathology , mechanical engineering , engineering
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 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 V ss 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, V ss nor t 1/2 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 AUC m /AUC p ‐ratios were similar at all dose levels for each metabolite. Values of t 1/2 for 341C90 were similar to those of 619C89 whereas t 1/2 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.