Safety, tolerability and pharmacokinetics (PK) of repeated doses of GSK573719 inhalation powder, a new long-acting muscarinic antagonist, in healthy adults

Abstract

Introduction: GSK573719 is a new long-acting muscarinic antagonist offering sustained 24-hour bronchodilation in development for the treatment of COPD. Objectives: To evaluate the safety, tolerability and PK of repeated once-daily doses (14 days) of GSK573719 dry powder inhalation (DPI). Methods: In this single-centre, double-blind, parallel-group study, 36 healthy adults were randomised 3:1 to GSK573719 (250μg, Cohort 1; 750μg, Cohort 2; 1000μg, Cohort 3) or placebo as DPI once daily for 14 days. Results: Most adverse events (AEs) were mild and all resolved during the study; the most frequent drug-related AEs were headache and pharyngolaryngeal pain (0–2 subjects per group). No clinically relevant abnormalities or changes were seen in laboratory results or vital signs. There were no clinically significant ECG abnormalities or heart rate changes. Although 41–67% of plasma PK samples were non-quantifiable, available data showed a median tmax of 5–15min, mean t1/2 (Day 14) of 26–28h (25–35h from urine PK). Although visual assessment of Ctau data suggested that steady state was achieved following 6 to 8 days of dosing, there was large data variability. Urinary excretion of unchanged GSK573719 was 1–1.5% of the total dose on Day 1 and 3.9–4.5% at steady state. Accumulation (Day 14:Day 1) was 1.5–3x based on plasma PK (3–4.5x on urine PK). There was no correlation between GSK573719 systemic exposure and pharmacodynamic variables. Conclusion: GSK573719 was well tolerated by all subjects and no safety concerns were identified even at the highest dose, supporting the continued development for COPD. Funded by GSK (AC4106889; [NCT00475436][1]) [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00475436&atom=%2Ferj%2F38%2FSuppl_55%2Fp3972.atom