title: Mass balance and metabolism of aclidinium bromide following intravenous administration of [¹⁴C]-aclidinium bromide in healthy subjects.
abstract: Aclidinium bromide is a novel, inhaled long-acting muscarinic antagonist with low systemic activity developed for the treatment of COPD. It is an ester compound rapidly hydrolysed in plasma into inactive alcohol and acid metabolites. In this Phase I, open-label study, the rates and routes of elimination of radioactivity following intravenous administration of [¹⁴C]-aclidinium bromide were determined. The metabolites of aclidinium were also characterized and identified in plasma and excreta. Twelve healthy males were randomized (1:1) to receive a single intravenous 400 µg dose of [phenyl-U-¹⁴C]- or [glycolyl-U-¹⁴C]-aclidinium bromide (via 5 min infusion) to label alcohol or acid metabolites of aclidinium, respectively. Safety and tolerability were assessed over a 9-day period. Following intravenous administration, the parent compound was rapidly hydrolysed into its acid and alcohol metabolites. Primary excretion routes for [phenyl-U-¹⁴C]- and [glycolyl-U-¹⁴C]-aclidinium were renal (urine: 65% and 54%, respectively; feces: 33% and 20%, respectively), with 1% excreted as unchanged aclidinium. A total of three treatment-emergent adverse events in two subjects were reported and were related to infusion site pain. Overall, aclidinium is rapidly hydrolysed into two main metabolites, which are predominantly excreted in urine. Aclidinium bromide 400 µg administered intravenously was safe and well tolerated in healthy subjects.
authors.affiliation: Forest Research Institute, Inc., Jersey City, New Jersey, USA. Stephan.Ortiz@frx.com
authors.forename: Stephan
authors.initials: S
authors.lastname: Ortiz
authors.forename: Stephen
authors.initials: S
authors.lastname: Flach
authors.forename: John
authors.initials: J
authors.lastname: Ho
authors.forename: Fanying
authors.initials: F
authors.lastname: Li
authors.forename: Cynthia F
authors.initials: CF
authors.lastname: Caracta
authors.forename: Esther Garcia
authors.initials: EG
authors.lastname: Gil
authors.forename: Josep M
authors.initials: JM
authors.lastname: Jansat
mesh_terms: D000328:Adult; D005243:Feces / Q000737:chemistry; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D018727:Muscarinic Antagonists / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D014326:Tropanes / Q000097:blood / Q000493:pharmacokinetics* / Q000652:urine; D055815:Young Adult
chemical_list: D018727:Muscarinic Antagonists; D014326:Tropanes; C542859:aclidinium bromide