title: 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.affiliation: Department of Pharmacokinetics and Dynamics, GlaxoWellcome, Beckenham, UK.
authors.forename: Z
authors.initials: Z
authors.lastname: Hussein
authors.forename: I J
authors.initials: IJ
authors.lastname: Fraser
authors.forename: K R
authors.initials: KR
authors.lastname: Lees
authors.forename: K W
authors.initials: KW
authors.lastname: Muir
authors.forename: M W
authors.initials: MW
authors.lastname: Lunnon
authors.forename: S F
authors.initials: SF
authors.lastname: Hobbiger
authors.forename: J
authors.initials: J
authors.lastname: Posner
mesh_terms: D000368:Aged; D002561:Cerebrovascular Disorders / Q000097:blood / Q000188:drug therapy / Q000378:metabolism*; D004311:Double-Blind Method; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008875:Middle Aged; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D010879:Piperazines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D011743:Pyrimidines / Q000008:administration & dosage / Q000097:blood / Q000493:pharmacokinetics*; D026941:Sodium Channel Blockers
chemical_list: D018696:Neuroprotective Agents; D010879:Piperazines; D011743:Pyrimidines; D026941:Sodium Channel Blockers; C081980:sipatrigine