Pharmacodynamics, pharmacokinetics and safety of GSK2190915, a novel oral anti-inflammatory 5-lipoxygenase-activating protein inhibitor.

ABSTRACT: To assess the pharmacokinetics, pharmacodynamics, safety and tolerability of the 5-lipoxygenase-activating protein inhibitor, GSK2190915, after oral dosing in two independent phase I studies, one in Western European and one in Japanese subjects, utilizing different formulations.Western European subjects received single (50-1000?mg) or multiple (10-450?mg) oral doses of GSK2190915 or placebo in a dose-escalating manner. Japanese subjects received three of four GSK2190915 doses (10-200?mg) plus placebo once in a four period crossover design. Blood samples were collected for GSK2190915 concentrations and blood and urine were collected to measure leukotriene B? and leukotriene E?, respectively, as pharmacodynamic markers of drug activity.There was no clear difference in adverse events between placebo and active drug-treated subjects in either study. Maximum plasma concentrations of GSK2190915 and area under the curve increased in a dose-related manner and mean half-life values ranged from 16-34?h. Dose-dependent inhibition of blood leukotriene B? production was observed and near complete inhibition of urinary leukotriene E? excretion was shown at all doses except the lowest dose. The EC?? values for inhibition of LTB? were 85?nM and 89?nM in the Western European and Japanese studies, respectively.GSK2190915 is well-tolerated with pharmacokinetics and pharmacodynamics in Western European and Japanese subjects that support once daily dosing for 24?h inhibition of leukotrienes. Doses of ?50?mg show near complete inhibition of urinary leukotriene E? at 24?h post-dose, whereas doses of ?150?mg are required for 24?h inhibition of blood LTB?.

SUBMITTER: Bain G 

PROVIDER: S-EPMC3575944 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature