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

ABSTRACT: 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.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??g OD) to 160?mL (glycopyrronium bromide 50??g 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??g, 50??g and 100??g, while the reverse was true for OD versus BID regimens from 12-24?hours. The 12.5??g BID dose produced a marginally higher improvement in trough FEV1 versus placebo than 50??g 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??g 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??g in patients with moderate-to-severe COPD.ClinicalTrials.gov: NCT01119950.

SUBMITTER: Arievich H

PROVIDER: S-EPMC3528484 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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

Arievich Helen H Overend Tim T Renard Didier D Gibbs Michael M Alagappan Vijay V Looby Michael M Banerji Donald D

BMC pulmonary medicine 20121208

<h4>Background</h4>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.<h4>Methods</h4>Double-blind, randomized, dose-finding trial with an eight-treatment, two-period, balanced incomplete block design. Patients (smoking history ≥10 pack-y ...[more]

PMID: 23217058

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Project description:One of the major causes of mortality all over the world is chronic obstructive pulmonary disease (COPD). Recently approved combined inhaler of formoterol fumarate (FF) and glycopyrronium bromide (GLY) has been used in very low concentrations (µg level/actuation) doses in COPD patients. The first spectrophotometric and advanced highly sensitive liquid chromatography has been achieved successfully throughout this study, permitting validated analysis of dual combined inhaler in raw material as well as pharmaceutical inhaled dosage form. Three sensitive analytical methods were carried out for the simultaneous assay of FF and GLY in their novel combined Metered dose inhaler (MDI). The first method depends on measuring the first derivative amplitudes at 208.27 nm for FF and at 213.27 nm and 239.86 nm for GLY, respectively. The second method depends on measurement of the first derivative of the ratio spectra at 214 or 229 nm for FF and 240 or 259 nm for GLY, respectively. For the spectrophotometric methods, the linearity ranges were 0.48-9.6 µg/mL for FF and 0.9-18 µg/mL for GLY. For the third method, valid ion-pairing chromatographic method was carried out applying C18 column and isocratic mobile phase of 60% v/v acetonitrile and 40% v/v deionized waster (pH 3.0) enclosing 0.025% sodium dodecyl sulfate, using UV detection adjusted to 210 nm and flow rate of 1.2 mL/min. For the ion-pairing chromatographic method, the linearity ranges were 0.048-4.8 µg/mL for FF and 0.09-9.0 µg/mL for GLY. The developed methods are reproducible, valid and offer efficient resolution between formoterol and glycopyrronium using spectrophotometric methods and highly sensitive and precise chromatographic method. The percent recoveries of the inhaled drugs in their MDI were good. The method was successfully established for the quantitative analysis of FF and GLY in their combined pharmaceutical inhaler capsules to validate the therapeutic efficiency of the combined drugs in quality control labs.

Dataset Information

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

Publications

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

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