Abstract
The metabolism and disposition of vilanterol, a novel long-acting β2-adrenoceptor agonist (LABA) for inhalation use, was investigated after oral administration in humans. Single oral administrations of up to 500 μg of vilanterol were shown to be safe and well tolerated in two clinical studies in healthy men. In a human radiolabel study, six healthy men received a single oral dose of 200 μg of [14C]vilanterol (74 kBq). Plasma, urine, and feces were collected up to 168 hours after the dose and were analyzed for vilanterol, metabolites, and radioactivity. At least 50% of the radioactive dose was orally absorbed. The primary route of excretion of drug-related material was via O-dealkylation to metabolites, which were mainly excreted in urine. Vilanterol represented a very small percentage (<0.5%) of the total drug-related material in plasma, indicative of extensive first-pass metabolism. Circulating metabolites resulted mainly from O-dealkylation and exhibited negligible pharmacologic activity. The therapeutic dose level for vilanterol is 25 μg by the inhalation route. At this low-dose level, the likelihood of pharmacologically inactive metabolites causing unexpected toxicity is negligible. In addition to providing an assessment of the disposition of vilanterol in human, this work highlights a number of complexities associated with determining human absorption, distribution, metabolism, and excretion (ADME) for inhaled molecules—mainly related to the low chemical doses and complications associated with the inhalation route of administration.
Footnotes
This work was funded by GlaxoSmithKline R&D, UK, as part of the development program for vilanterol as a novel therapeutic agent. Data in this manuscript correspond with clinical study numbers B2C106180 (GSK company report GM2009/00020/00) and B2C106181 (GSK company report YM2010/00088/00) with metabolite identifications reported in study number 10DMW020 (GSK company report 2011N115614). Hepatocyte incubations were reported in GSK company report WD2006/02574/00. Pharmacologic activities of metabolites were reported in GSK company report HR2008/00016/00. All authors were employees of GlaxoSmithKline Research and Development Ltd. at the time of conducting the work.
Primary Laboratory of Origin: Drug Metabolism and Pharmacokinetics Division, GlaxoSmithKline Research and Development Ltd., Park Road, Ware, United Kingdom
- Received August 30, 2012.
- Accepted October 4, 2012.
- Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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