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

Double-blind, randomized, dose-finding trial with an eight-treatment, two-period, balanced incomplete block design. Patients (smoking history ≥10 pack-years, post-bronchodilator FEV1 ≥30% and <80% predicted, FEV1/FVC <0.7) were randomized to one of 16 independent sequences for 28？days. Primary endpoint: mean trough FEV1 at Day 28.385 patients (mean age 61.2？years; mean post-bronchodilator FEV1 53% predicted) were randomized; 88.6% completed. All OD and BID dosing regimens produced dose-dependent bronchodilation; at Day 28, increases in mean trough FEV1 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 FEV1 at steady-state in favour of BID dosing. Over 24？hours, separation between OD and BID regimens was even smaller (FEV1 AUC0-24h maximum difference for equivalent daily dose regimens: 8？mL). Dose–response results for FEV1 at 12？hours, FEV1 AUC0-12h and FEV1 AUC0-4h 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 FEV1 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.Glycopyrronium bromide 50？μg OD provides significant bronchodilation over a 24？hour period, and in terms of FEV1 AUC0-24h 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 pati