A novel model-based approach for dose determination of glycopyrronium bromide in COPD

BACKGROUND: Glycopyrronium bromide (NVA237) is an inhaled long-acting muscarinic antagonist in development for treatment of COPD. This study compared the efficacy and safety of once-daily (OD) and twice-daily (BID) glycopyrronium bromide regimens, using a novel model-based approach, in patients with moderate-to-severe COPD. METHODS: Double-blind, randomized, dose-finding trial with an eight-treatment, two-period, balanced incomplete block design. Patients (smoking history ≥10 pack-years, post-bronchodilator FEV(1) ≥30% and <80% predicted, FEV(1)/FVC <0.7) were randomized to one of 16 independent sequences for 28 days. Primary endpoint: mean trough FEV(1) at Day 28. RESULTS: 385 patients (mean age 61.2 years; mean post-bronchodilator FEV(1) 53% predicted) were randomized; 88.6% completed. All OD and BID dosing regimens produced dose-dependent bronchodilation; at Day 28, increases in mean trough FEV(1) versus placebo were statistically significant for all regimens, ranging from 51 mL (glycopyrronium bromide 12.5 μg OD) to 160 mL (glycopyrronium bromide 50 μg BID). Pharmacodynamic steady-state was reached by Day 7. There was a small separation (≤37 mL) between BID and OD dose–response curves for mean trough FEV(1) at steady-state in favour of BID dosing. Over 24 hours, separation between OD and BID regimens was even smaller (FEV(1) AUC(0-24h) maximum difference for equivalent daily dose regimens: 8 mL). Dose–response results for FEV(1) at 12 hours, FEV(1) AUC(0-12h) and FEV(1) AUC(0-4h) at steady-state showed OD regimens provided greater improvement over placebo than BID regimens for total daily doses of 25 μg, 50 μg and 100 μg, while the reverse was true for OD versus BID regimens from 12–24 hours. The 12.5 μg BID dose produced a marginally higher improvement in trough FEV(1) versus placebo than 50 μg OD, however, the response at 12 hours over placebo was suboptimal (74 mL). Glycopyrronium bromide was safe and well tolerated at all doses. CONCLUSIONS: Glycopyrronium bromide 50 μg OD provides significant bronchodilation over a 24 hour period, and in terms of FEV(1) AUC(0-24h) is not significantly different than the same total daily dose administered BID. Importantly, OD dosing may confer better patient adherence. The results are consistent with previous glycopyrronium bromide studies and support once-daily dosing of glycopyrronium bromide 50 μg in patients with moderate-to-severe COPD. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01119950