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

Authors: HUSSEIN, Z.¹; FRASER, I. J.¹; LEES, K. R.²; MUIR, K. W.²; LUNNON, M. W.¹; HOBBIGER, S. F.¹; POSNER, J.¹

Source: British Journal of Clinical Pharmacology, Volume 41, Number 6, June 1996 , pp. 505-511(7)

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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⁻¹kg⁻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). GeometricV_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 nort_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 oft_1/2 for 341C90 were similar to those of 619C89 whereast_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.

Keywords: 619C89; 341C90; 78C90; stroke; pharmacokinetics

Document Type: Research article

DOI: http://dx.doi.org/10.1046/j.1365-2125.1996.03625.x

Affiliations: 1: GlaxoWellcome, Beckenham, 2: Acute Stroke Unit, Western Infirmary, Glasgow, UK

Publication date: 1996-06-01

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

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