a novel model-based approach for dose determination of glycopyrronium bromide in copd一种新颖的基于模型的方法剂量测定格隆溴铵在慢性阻塞性肺病.pdfVIP

Arievich et al. BMC Pulmonary Medicine 2012, 12:74 /1471-2466/12/74 RESEARCH ARTICLE Open Access A novel model-based approach for dose determination of glycopyrronium bromide in COPD 1 2* 3 2 2 3 Helen Arievich , Tim Overend , Didier Renard , Michael Gibbs , Vijay Alagappan , Michael Looby and Donald Banerji4 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 FEV ≥30% and 80% predicted, FEV / 1 1 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