Characterization of the bronchodilatory dose response to indacaterol in patients with chronic obstructive pulmonary disease using model-based approaches.
Summary of "Characterization of the bronchodilatory dose response to indacaterol in patients with chronic obstructive pulmonary disease using model-based approaches."
Indacaterol is a once-daily long-acting inhaled beta2-agonist indicated for maintenance treatment of moderate-to-severe chronic obstructive pulmonary disease (COPD). The large inter-patient and inter-study variability in forced expiratory volume in 1 second (FEV1) with bronchodilators makes determination of optimal doses difficult in conventional dose-ranging studies. We considered alternative methods of analysis.
We utilized a novel modelling approach to provide a robust analysis of the bronchodilatory dose response to indacaterol. This involved pooled analysis of study-level data to characterize the bronchodilatory dose response, and nonlinear mixed-effects analysis of patient-level data to characterize the impact of baseline covariates.
The study-level analysis pooled summary statistics for each steady-state visit in 11 placebo-controlled studies. These study-level summaries encompassed data from 7476 patients at indacaterol doses of 18.75-600 ug once daily, and showed that doses of 75 ug and above achieved clinically important improvements in predicted trough FEV1 response. Indacaterol 75 ug achieved 74% of the maximum effect on trough FEV1, and exceeded the midpoint of the 100-140 mL range that represents the minimal clinically important difference (MCID; [greater than or equal to]120 mL vs placebo), with a 90% probability that the mean improvement vs placebo exceeded the MCID. Indacaterol 150 ug achieved 85% of the model-predicted maximum effect on trough FEV1 and was numerically superior to all comparators (99.9% probability of exceeding MCID). Indacaterol 300 ug was the lowest dose that achieved the model-predicted maximum trough response. The patient-level analysis included data from 1835 patients from two dose-ranging studies of indacaterol 18.75-600 ug once daily. This analysis provided a characterization of dose response consistent with the study-level analysis, and demonstrated that disease severity, as captured by baseline FEV1, significantly affects the dose response, indicating that patients with more severe COPD require higher doses to achieve optimal bronchodilation.
Comprehensive assessment of the bronchodilatory dose response of indacaterol in COPD patients provided a robust confirmation that 75 ug is the minimum effective dose, and that 150 and 300 ug are expected to provide optimal bronchodilation, particularly in patients with severe disease.
This article was published in the following journal.
Name: Respiratory research
- PubMed Source: http://www.ncbi.nlm.nih.gov/pubmed/21518459
- DOI: http://dx.doi.org/10.1186/1465-9921-12-54
Medical and Biotech [MESH] Definitions
Dose-response Relationship, Immunologic
A specific immune response elicited by a specific dose of an immunologically active substance or cell in an organism, tissue, or cell.
Maximum Tolerated Dose
The highest dose of a biologically active agent given during a chronic study that will not reduce longevity from effects other than carcinogenicity. (from Lewis Dictionary of Toxicology, 1st ed)
Dose-response Relationship, Radiation
The relationship between the dose of administered radiation and the response of the organism or tissue to the radiation.
Dose-response Relationship, Drug
The relationship between the dose of an administered drug and the response of the organism to the drug.
Lethal Dose 50
The dose amount of poisonous or toxic substance or dose of ionizing radiation required to kill 50% of the tested population.
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