GSK2190915 is a high affinity 5-lipoxygenase-activating protein (FLAP) inhibitor that attenuates the production of leukotrienes through the blockage of the first step in the leukotriene pathway, 5-lipoxygenase (5-LO) activation. Leukotrienes are potent inflammatory molecules produced mainly by mast cells, eosinophils, monocytes/macrophage and neutrophils in response to allergic or inflammatory stimuli. GSK2190915 inhibits the production of leukotriene B4 (LTB4) and cysteinyl leukotrienes (cysLTs).~This is an open label, 4-way, 4 treatment period, non-randomised, single-dose crossover study with an interim analysis following the third treatment period. The GSK2190915 formulations used are: milled 100mg and 200mg tablets, a 100mg enteric-coated tablet, and a [14C] radiolabelled GSK2190915 intravenous solution.~There will be 4 periods. Period 1 includes two cohorts (of 7 subjects each), both of which will be administered the 100mg GSK2190915 milled tablet orally; however, the second cohort will in addition be dosed with an intravenous radiolabelled infusion of the drug. In the second period, a 100mg dose of milled GSK2190915 tablet (a ground half of a 200mg tablet) is administered directly to the proximal small bowel using an Enterion capsule. The same dose is repeated in the third period, but is administered directly to the distal small bowel. An interim analysis will then follow. The decision to proceed will be made following a review of the pharmacokinetic data from the first three treatments. In the fourth and final period, the treatment will be a 100mg enteric-coated tablet of GSK2190915 administered orally. There will be a minimum washout of 7 days in between each period.~This study aims to determine the pharmacokinetics and absolute bioavailability of GSK2190915 to enable optimisation of suitable formulations to be used in clinical development. Periods 1 to 3 will characterise the absolute bioavailability of GSK2190915 using IV tracer and oral formulation, in addition to defining the regional absorption characteristics of the drug when released in the proximal and distal parts of the gastro-intestinal tract. The fourth period will investigate the oral bioavailability of an enteric coated formulation of GSK2190915.~Fourteen subjects will be dosed to ensure data in 10 at the end of the clinical study. Seven of the subjects (in cohort 2, Period 1) will receive an IV microtracer in addition to the other treatments.
GSK2190915 is a high affinity 5-lipoxygenase-activating protein (FLAP) inhibitor that attenuates the production of leukotrienes through the blockage of the first step in the leukotriene pathway, 5-lipoxygenase (5-LO) activation. GSK2190915 inhibits the production of leukotriene B4 (LTB4) and cysteinyl leukotrienes (cysLTs).~This is an open label, 4-way, 4-treatment period, non-randomised, crossover study with an interim analysis. The GSK2190915 formulations used in this study will be: a 100mg and 200mg milled tablet, a 100mg enteric-coated tablet, and a [14C] radiolabelled GSK2190915 intravenous solution.~This study aims to determine the pharmacokinetics and absolute bioavailability of GSK2190915 to enable optimisation of suitable formulations to be used in clinical development Fourteen subjects will be dosed to ensure data in 10 at the end of the clinical study. Seven of the subjects will receive an IV microtracer in addition to the other treatments.