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Safety and Tolerability of Aclidinium Administered Intravenously and Absolute Bioavailability of Inhaled Aclidinium in Healthy Male Participants
Author(s) -
Ortiz Stephan,
Flach Stephen,
Caracta Cynthia,
Gil Esther Garcia,
Jansat Josep M.
Publication year - 2012
Publication title -
the journal of clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.92
H-Index - 116
eISSN - 1552-4604
pISSN - 0091-2700
DOI - 10.1177/0091270011406281
Subject(s) - tolerability , bioavailability , pharmacokinetics , crossover study , pharmacology , medicine , pharmacodynamics , placebo , anesthesia , adverse effect , alternative medicine , pathology
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.