PMID- 22366196 OWN - NLM STAT- MEDLINE DCOM- 20120723 LR - 20121115 IS - 1522-9629 (Electronic) IS - 1094-5539 (Linking) VI - 25 IP - 2 DP - 2012 Apr TI - Safety and pharmacokinetics of multiple doses of aclidinium bromide administered twice daily in healthy volunteers. PG - 193-9 LID - 10.1016/j.pupt.2012.02.002 [doi] AB - Chronic obstructive pulmonary disease (COPD) is characterized by progressive airway obstruction and increased cholinergic tone. The global initiative for chronic obstructive lung disease (GOLD) guidelines recommend long-acting anticholinergics for COPD maintenance treatment. Aclidinium bromide is a novel, long-acting muscarinic antagonist developed for the treatment of COPD. A phase I, randomized, single-blind, multiple-dose clinical trial was conducted to assess the safety and pharmacokinetics (PK) of multiple doses of twice-daily (BID) aclidinium in healthy subjects. Thirty healthy male and female subjects received aclidinium 200 mug, 400 mug, 800 mug, or placebo twice daily for 7 days. Subjects were randomized to 1 of 3 cohorts and 10 subjects in each cohort were randomized (8:2) to either aclidinium or placebo groups. Safety was assessed via adverse events (AEs), laboratory evaluations, vital signs, and ECGs. Plasma samples were obtained at multiple time points throughout the study and analyzed for aclidinium and its inactive acid and alcohol metabolites using a fully validated method of liquid chromatography coupled with tandem mass spectrometry. A total of 9 treatment-emergent AEs were reported (1, placebo; 3, aclidinium 400 mug; 5, aclidinium 800 mug), all of which were mild in severity. No serious AEs were reported. There were no clinically meaningful changes in laboratory parameters or vital signs. PK parameters on Day 7 following BID dosing of aclidinium showed that steady state was achieved for aclidinium and its metabolites. On Days 1 and 7, maximum plasma concentrations (Cmax) of aclidinium were generally observed at the first PK time point (5 min postdose) and rapidly declined, with plasma concentrations generally less than 10% of Cmax by 6 h postdose in all aclidinium groups. Mean effective t((1/2)) after the evening dose on Day 7 ranged from 4.6 to 7.0 h for aclidinium 400 mug and 800 mug, similar to the terminal t((1/2)) observed on Day 1 (4.5-5.9 h). Exposure for aclidinium and both metabolites increased with increasing dose, with the increase in exposure being less than dose proportional between the 400 mug and 800 mug doses. Overall, all doses of aclidinium were safe and well tolerated throughout the study. Pharmacokinetic steady state was reached for aclidinium and both metabolites within the 7-day treatment period for all doses tested. Aclidinium bromide exhibited time-independent PK following dosing to steady state, indicating that similar concentration versus time profiles will occur after repeated administration at the same dose and frequency. CI - Copyright A(c) 2012 Elsevier Ltd. All rights reserved. FAU - Lasseter, K AU - Lasseter K AD - Clinical Pharmacology of Miami, Inc., 550 West 84th Street, Miami, FL 33014, USA. klasseter@clinpharmmiami.com FAU - Dilzer, S AU - Dilzer S FAU - Jansat, J M AU - Jansat JM FAU - Garcia Gil, E AU - Garcia Gil E FAU - Caracta, C F AU - Caracta CF FAU - Ortiz, S AU - Ortiz S LA - eng PT - Clinical Trial, Phase I PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, Non-U.S. Gov't DEP - 20120215 PL - England TA - Pulm Pharmacol Ther JT - Pulmonary pharmacology & therapeutics JID - 9715279 RN - 0 (Muscarinic Antagonists) RN - 0 (Tropanes) RN - UQW7UF9N91 (aclidinium bromide) SB - IM MH - Adolescent MH - Adult MH - Chromatography, Liquid MH - Cohort Studies MH - Dose-Response Relationship, Drug MH - Female MH - Half-Life MH - Humans MH - Male MH - Middle Aged MH - Muscarinic Antagonists/*administration & dosage/adverse effects/pharmacokinetics MH - Single-Blind Method MH - Tandem Mass Spectrometry MH - Time Factors MH - Tropanes/*administration & dosage/adverse effects/pharmacokinetics MH - Young Adult EDAT- 2012/03/01 06:00 MHDA- 2012/07/24 06:00 CRDT- 2012/02/28 06:00 PHST- 2011/09/22 00:00 [received] PHST- 2012/01/20 00:00 [revised] PHST- 2012/02/08 00:00 [accepted] PHST- 2012/02/28 06:00 [entrez] PHST- 2012/03/01 06:00 [pubmed] PHST- 2012/07/24 06:00 [medline] AID - S1094-5539(12)00026-0 [pii] AID - 10.1016/j.pupt.2012.02.002 [doi] PST - ppublish SO - Pulm Pharmacol Ther. 2012 Apr;25(2):193-9. doi: 10.1016/j.pupt.2012.02.002. Epub 2012 Feb 15.