Effects of Urotensin II Receptor Antagonist, GSK1440115, in Asthma.

ABSTRACT: BACKGROUND:Urotensin II (U-II) is highly expressed in the human lung and has been implicated in regulating respiratory physiology in preclinical studies. Our objective was to test antagonism of the urotensin (UT) receptor by GSK1440115, a novel, competitive, and selective inhibitor of the UT receptor, as a therapeutic strategy for the treatment of asthma. METHODS:Safety, tolerability, and pharmacokinetics (PK) of single doses of GSK1440115 (1-750?mg) were assessed in a Phase I, placebo controlled study in 70 healthy subjects. In a Phase Ib study, 12 asthmatic patients were randomized into a two-period, single-blind crossover study and treated with single doses of 750?mg GSK1440115 or placebo and given a methacholine challenge. RESULTS:Administration of GSK1440115 was safe and well-tolerated in healthy subjects and asthmatic patients. In both studies, there was a high degree of variability in the observed PK following oral dosing with GSK1440115 at all doses. There was a marked food effect in healthy subjects at the 50?mg dose. In the presence of food at the 750?mg dose, the time to maximal concentration was between 2 and 6?h and the terminal half-life was short at approximately 2?h. All asthmatic patients maintained greater than the predicted concentration levels necessary to achieve predicted 96% receptor occupancy for ?3?h (between 4 and 7?h post-dose). There were no apparent trends or relationships between the systemic plasma exposure of GSK1440115 and pharmacodynamic endpoints, PC20 after methacholine challenge and FEV1, in asthmatics. CONCLUSION:While GSK1440115 was safe and well-tolerated, it did not induce bronchodilation in asthmatics, or protect against methacholine-induced bronchospasm, suggesting that acute UT antagonism is not likely to provide benefit as an acute bronchodilator in this patient population.

SUBMITTER: Portnoy A 

PROVIDER: S-EPMC3638148 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature