Metabolism and Disposition of Vilanterol, a Long-Actingβ₂-Adrenoceptor Agonist for Inhalation Use in Humans

Abstract

The metabolism and disposition of vilanterol, a novel long-acting b 2 -adrenoceptor agonist (LABA) for inhalation use, was investigated after oral administration in humans. Single oral administrations of up to 500 mg 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 mg of [ 14 C]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 firstpass metabolism. Circulating metabolites resulted mainly from Odealkylation and exhibited negligible pharmacologic activity. The therapeutic dose level for vilanterol is 25 mg 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.

Umeclidinium Bromide and Vilanterol Trifenatate Inhalation Powder

“…1,4,7,8,[10][11][12][13][14] There was no difference in vilanterol T max when delivered as monotherapy or in combination. 12 The steady state of umeclidinium/vilanterol is achieved within 14 days, with 1.8-and 1.7-fold accumulation, respectively.…”

“…The effective half-life of both umeclidinium and vilanterol is 11 hours. 1,13 In patients with moderate hepatic impairment given umeclidinium or vilanterol, there was no increase in exposure or changes in protein binding. In patients with severe renal impairment (creatinine clearance [CrCl] less than 30 mL/min), umeclidinium exposure did not increase and vilanterol exposure increased by 56% compared with healthy patients; additionally, there were no changes in protein binding.…”

“…Vilanterol is metabolized to a range of metabolites with significantly reduced beta-1 and beta-2 agonist activity. 1,13 Following IV administration of radiolabeled umeclidinium, 58% was recovered in feces and 22% 1,10 Following oral administration of radiolabeled vilanterol, 70% was recovered in urine and 30% in feces. The effective half-life of both umeclidinium and vilanterol is 11 hours.…”

New bronchodilators in treatment of chronic obstructive pulmonary disease

“…Vilanterol (GW642444), a novel LABA used via inhalation [7]. In a randomized placebo controlled study 602 COPD patients were evaluated.…”

Disposition and Metabolism of Darapladib, a Lipoprotein-Associated Phospholipase A2 Inhibitor, in Humans

“…The increased availability and acceptance of AMS within the pharmaceutical industry (Smith 2011;Iyer et al, 2012;Lappin et al, 2012;Vuong et al, 2012;Bowers et al, 2013;Harrell et al, 2013) does facilitate replacing the traditional single-dose human radiolabeled study with a design using repeated therapeutic doses incorporating trace levels of radioactivity amenable to AMS detection, which in …”