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Pharmacodynamics, pharmacokinetics and safety of GSK2190915, a novel oral anti-inflammatory 5-lipoxygenase-activating protein inhibitor
- Source :
- British journal of clinical pharmacology. 75(3)
- Publication Year :
- 2012
-
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 B₄ and leukotriene E₄, 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 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.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.
- Subjects :
- Adult
Leukotriene E4
Male
Cross-Over Studies
Indoles
Adolescent
Dose-Response Relationship, Drug
Administration, Oral
Middle Aged
Leukotriene B4
White People
Young Adult
Asian People
Double-Blind Method
Pharmacodynamics
5-Lipoxygenase-Activating Protein Inhibitors
Area Under Curve
Humans
Female
Pentanoic Acids
Biomarkers
Aged
Subjects
Details
- ISSN :
- 13652125
- Volume :
- 75
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- British journal of clinical pharmacology
- Accession number :
- edsair.pmid..........54065709d27d2c330210a637946a2dc1