Abstract
The metabolism and disposition of vilanterol, a novel long-acting beta2 adrenoceptor agonist (LABA) for inhalation use, was investigated following oral administration to human. Single oral administrations of up to 500 μg vilanterol were shown to be safe and well tolerated in two clinical studies using healthy male subjects. In a human radiolabel study, six healthy male subjects received a single oral dose of 200 μg [14C] vilanterol (74 kBq). Plasma, urine and faeces were collected up to 168 hours post dose and analysed 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 pharmacological 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 ADME for inhaled molecules - mainly related to the low chemical doses and complications associated with the inhalation route of administration.
- absorption
- drug absorption
- drug clearance
- drug disposition
- first-pass metabolism
- hepatocytes
- human pharmacokinetics
- inhaled drugs
- metabolite identification
- stable isotopes
- Received August 30, 2012.
- Accepted October 4, 2012.
- The American Society for Pharmacology and Experimental Therapeutics