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

Abstract

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 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.

Results: 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.

Conclusions: 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 patients with moderate-to-severe COPD.

Trial registration: ClinicalTrials.gov: NCT01119950.

Figures

Figure 1

Trough FEV1dose−response results at 24 hours at steady-state (modified intent-to-treat population). Model average placebo-adjusted values for OD and BID dosing regimens, with 90% confidence limits (red and blue shaded areas, respectively). FEV1: forced expiratory volume in one second; OD: once daily; BID: twice daily.

Figure 2

Dose−response results of FEV1AUC0-24hat steady-state (modified intent-to-treat population). Model average placebo-adjusted values for OD and BID dosing regimens, with 90% confidence limits (red and blue shaded areas, respectively). FEV1: forced expiratory volume in one second; AUC: area under the curve; OD: once daily; BID: twice daily.

Figure 3

Dose−response results of peak FEV1at steady-state (modified intent-to-treat population). Model average values for OD and BID dosing regimens, with 90% confidence limits (red and blue shaded areas, respectively). FEV1: forced expiratory volume in one second; OD: once daily; BID: twice daily.

Figure 4

24-hour spirometry results at steady-state (modified intent-to-treat population). Model-based placebo-adjusted values for OD and BID dosing regimens, with 90% confidence limits (red and blue shaded areas, respectively). MCID = 100 mL [12]. MCID: minimal clinically important difference; FEV1: forced expiratory volume in one second; OD: once daily; BID: twice daily.