Front. Pharmacol., 29 April 2013 |doi:10.3389/fphar.2013.00054
Effects of urotensin II receptor antagonist, GSK1440115, in asthma
- 1Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, King of Prussia, PA, USA
- 2Heart Failure Discovery Performance Unit, GlaxoSmithKline, King of Prussia, PA, USA
- 3Clinical Pharmacology Modeling and Simulation, GlaxoSmithKline, King of Prussia, PA, USA
- 4Quantitative Sciences, GlaxoSmithKline, Collegeville, PA, USA
- 5Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, Research Triangle Park, NC, USA
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, PC20after 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.
Keywords: urotensin II, asthma, receptor antagonist
Citation: Portnoy A, Kumar S, Behm DJ, Mahar KM, Noble RB, Throup JP and Russ SF (2013) Effects of urotensin II receptor antagonist, GSK1440115, in asthma. Front. Pharmacol.4:54. doi: 10.3389/fphar.2013.00054
Received: 05 February 2013; Accepted: 10 April 2013;
Published online: 29 April 2013.
Published online: 29 April 2013.
Edited by:
Pascal Chanez, Universite de la Mediterranée, France
Copyright: © 2013 Portnoy, Kumar, Behm, Mahar, Noble, Throup and Russ. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in other forums, provided the original authors and source are credited and subject to any copyright notices concerning any third-party graphics etc.
*Correspondence: Sanjay Kumar, Virtual Proof of Concept Discovery Performance Unit, GlaxoSmithKline, 709 Swedeland Road, UW2230, King of Prussia, PA 19406-0939, USA. e-mail: sanjay.2.kumar@gsk.com
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