TY - JOUR T1 - Repeated-dose pharmacokinetics of once-daily TD-4208, a long-acting muscarinic receptor antagonist (LAMA), in subjects with COPD JF - European Respiratory Journal JO - Eur Respir J VL - 44 IS - Suppl 58 SP - 1892 AU - David Bourdet AU - Chris Barnes AU - Wayne Yates AU - Ed Moran AU - Andrew Nicholls AU - Brett Haumann Y1 - 2014/09/01 UR - http://erj.ersjournals.com/content/44/Suppl_58/1892.abstract N2 - IntroductionTD-4208 is a lung-selective, LAMA shown to have a long duration of action and minimal systemic antimuscarinic activity in subjects with COPD after single and repeated-dose, once-daily, inhaled administration. The current study evaluates the pharmacokinetics of nebulized TD-4208 and its major metabolite (THRX-195518) in subjects with moderate to severe COPD.MethodsFifty-nine subjects with moderate to severe COPD were randomized in a double-blind, incomplete block 5-way crossover study. TD-4208 (22, 44, 88, 175, 350, 750 µg) or matching placebo was administered via an inhalation solution by PARI nebulizer in the morning of each day for 7 days followed by a 14-day washout between each treatment period.ResultsTD-4208 demonstrated rapid absorption (median tmax∼ 15 min) followed by a steep, bi-exponential decline resulting in low systemic plasma concentrations. Metabolic conversion to THRX-195518 occurred rapidly and extensively. TD-4208 and THRX-195518 demonstrated linear increases in plasma exposure with dose. The metabolite-to-parent ratio ranged from 3.3 to 9.7 on Day 7. TD-4208 and THRX-195518 elimination profiles were similar and were characterized by a terminal elimination half-life ranging from 22.3 to 25.3 h. Accumulation of TD-4208 and THRX-195518 in plasma was limited (< 1.6-fold) and steady-state was achieved by Day 7.ConclusionsLow systemic exposures of TD-4208 and its major metabolite were observed after inhaled administration, consistent with the lack of systemic antimuscarinic activity. TD-4208 exhibits a predictable dose-dependent plasma pharmacokinetic profile indicative of reproducible nebulized delivery of TD-4208. ER -