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

ABSTRACT

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 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).

4Average 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.

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.