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

Aim 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. Method Western European subjects received single (501000mg) or multiple (10450mg) oral doses of GSK2190915 or placebo in a dose-escalating manner. Japanese subjects received three of four GSK2190915 doses (10200mg) 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 B4 and leukotriene E4, respectively, as pharmacodynamic markers of drug activity. Results 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 1634h. Dose-dependent inhibition of blood leukotriene B4 production was observed and near complete inhibition of urinary leukotriene E4 excretion was shown at all doses except the lowest dose. The EC50 values for inhibition of LTB4 were 85nm and 89nm in the Western European and Japanese studies, respectively. Conclusion GSK2190915 is well-tolerated with pharmacokinetics and pharmacodynamics in Western European and Japanese subjects that support once daily dosing for 24h inhibition of leukotrienes. Doses of 50mg show near complete inhibition of urinary leukotriene E4 at 24h post-dose, whereas doses of 150mg are required for 24h inhibition of blood LTB4.