title: Safety and tolerability of aclidinium administered intravenously and absolute bioavailability of inhaled aclidinium in healthy male participants.
abstract: Aclidinium bromide is a long-acting muscarinic antagonist in development for chronic obstructive pulmonary disease treatment. This 2-part, phase I study evaluated the safety and tolerability of single ascending intravenous (IV) doses of aclidinium to determine its maximum tolerated dose (MTD; part I) and its absolute bioavailability (part II). Healthy male participants (N = 24) were randomized (1:1) in each part: 3-period crossover, placebo-controlled, single-ascending, alternating IV doses of aclidinium (25-400 µg) in part I and 2-period crossover, single-alternating IV and inhaled doses of aclidinium (200 µg) in part II. A ≥7-day washout separated treatment periods. Pharmacokinetic data were collected in both parts. Following IV or inhaled aclidinium, time to reach maximum plasma concentration following drug administration (t(max) ) was 5 to 7 minutes for all doses. After maximum plasma drug concentration (C(max)), aclidinium was rapidly cleared from plasma. Aclidinium absolute bioavailability was <5% following a single inhaled 200-µg dose. Urinary excretion of unchanged aclidinium was very low, with a greater amount of inactive metabolites excreted compared with aclidinium, all of which were recovered within 12 hours postdose. The MTD following IV administration was not reached; all single IV (25-400 µg) and inhaled doses (200 µg) were well tolerated. In conclusion, the low and short-lived bioavailability of aclidinium and the low incidence of systemic side effects contribute to its positive safety and tolerability profile.
authors.affiliation: Forest Research Institute, Jersey City, NJ 07311, 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: Cynthia
authors.initials: C
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: D000280:Administration, Inhalation; D000328:Adult; D001682:Biological Availability; D001711:Biotransformation; D001769:Blood / Q000378:metabolism; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D006207:Half-Life; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D018727:Muscarinic Antagonists / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics*; D029424:Pulmonary Disease, Chronic Obstructive / Q000188:drug therapy; D016037:Single-Blind Method; D014326:Tropanes / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism / Q000493:pharmacokinetics*; D014556:Urine / Q000737:chemistry; D055815:Young Adult
chemical_list: D018727:Muscarinic Antagonists; D014326:Tropanes; C542859:aclidinium bromide