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


METHODS
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 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 16-34 h. 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 85 nM and 89 nM in the Western European and Japanese studies, respectively.


CONCLUSIONS
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 E₄ at 24 h post-dose, whereas doses of ≥150 mg are required for 24 h inhibition of blood LTB₄.
Bristol-Myers Squibb, San Diego, CA 92121, USA. gretchen.bain@bms.com
Gretchen
G
Bain
Christopher D
CD
King
Kevin
K
Schaab
Melissa
M
Rewolinski
Virginia
V
Norris
Claire
C
Ambery
Jane
J
Bentley
Masanori
M
Yamada
Angelina M
AM
Santini
Jeroen
J
van de Wetering de Rooij
Nicholas
N
Stock
Jasmine
J
Zunic
John H
JH
Hutchinson
Jilly F
JF
Evans
D058946:5-Lipoxygenase-Activating Protein Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D000284:Administration, Oral; D000293:Adolescent; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D044466:Asian People; D015415:Biomarkers / Q000097:blood / Q000652:urine; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D007975:Leukotriene B4 / Q000097:blood / Q000652:urine; D017999:Leukotriene E4 / Q000097:blood* / Q000652:urine; D008297:Male; D008875:Middle Aged; D010421:Pentanoic Acids / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology; D044465:White People; D055815:Young Adult
C552410:3-(3-tert-butylsulfanyl-1-(4-(6-ethoxypyridin-3-yl)benzyl)-5-(5-methylpyridin-2-ylmethoxy)-1H-indol-2-yl)-2,2-dimethylpropionic acid; D058946:5-Lipoxygenase-Activating Protein Inhibitors; D015415:Biomarkers; D007211:Indoles; D010421:Pentanoic Acids; D007975:Leukotriene B4; D017999:Leukotriene E4