Limits...
Characterization of the bronchodilatory dose response to indacaterol in patients with chronic obstructive pulmonary disease using model-based approaches.

Renard D, Looby M, Kramer B, Lawrence D, Morris D, Stanski DR - Respir. Res. (2011)

Bottom Line: 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.Indacaterol 300 μg 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 μg once daily.

View Article: PubMed Central - HTML - PubMed

Affiliation: Novartis Pharma AG, Basel, Switzerland. didier.renard@novartis.com

ABSTRACT

Background: Indacaterol is a once-daily long-acting inhaled β2-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.

Methods: 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.

Results: 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 μg once daily, and showed that doses of 75 μg and above achieved clinically important improvements in predicted trough FEV1 response. Indacaterol 75 μg 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; ≥120 mL vs placebo), with a 90% probability that the mean improvement vs placebo exceeded the MCID. Indacaterol 150 μg 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 μg 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 μg 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.

Conclusions: Comprehensive assessment of the bronchodilatory dose response of indacaterol in COPD patients provided a robust confirmation that 75 μg is the minimum effective dose, and that 150 and 300 μg are expected to provide optimal bronchodilation, particularly in patients with severe disease.

Show MeSH

Related in: MedlinePlus

Three dimensional representation of predicted trough FEV1 improvement at steady state for typical COPD patient as a function of dose and baseline value.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3102616&req=5

Figure 7: Three dimensional representation of predicted trough FEV1 improvement at steady state for typical COPD patient as a function of dose and baseline value.

Mentions: The patient-level model quantifies this overall relationship precisely and demonstrates that both the maximum response (Emax) and the sensitivity (ED50) to a bronchodilator are strongly influenced by the baseline FEV1. In other words, as disease severity increases (i.e. baseline FEV1 decreases), patients require higher doses to obtain an optimal response. This relationship can be seen in a three dimensional display (figure 7), which highlights the dependency of the trough FEV1 response on both dose and baseline FEV1 and shows that as baseline FEV1 increases, the dose-response curve becomes steeper and reaches a higher maximum level. This analysis suggests that the heterogeneity observed in a typical COPD population may require a more differentiated approach to tailoring therapy to disease status.


Characterization of the bronchodilatory dose response to indacaterol in patients with chronic obstructive pulmonary disease using model-based approaches.

Renard D, Looby M, Kramer B, Lawrence D, Morris D, Stanski DR - Respir. Res. (2011)

Three dimensional representation of predicted trough FEV1 improvement at steady state for typical COPD patient as a function of dose and baseline value.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3102616&req=5

Figure 7: Three dimensional representation of predicted trough FEV1 improvement at steady state for typical COPD patient as a function of dose and baseline value.
Mentions: The patient-level model quantifies this overall relationship precisely and demonstrates that both the maximum response (Emax) and the sensitivity (ED50) to a bronchodilator are strongly influenced by the baseline FEV1. In other words, as disease severity increases (i.e. baseline FEV1 decreases), patients require higher doses to obtain an optimal response. This relationship can be seen in a three dimensional display (figure 7), which highlights the dependency of the trough FEV1 response on both dose and baseline FEV1 and shows that as baseline FEV1 increases, the dose-response curve becomes steeper and reaches a higher maximum level. This analysis suggests that the heterogeneity observed in a typical COPD population may require a more differentiated approach to tailoring therapy to disease status.

Bottom Line: 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.Indacaterol 300 μg 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 μg once daily.

View Article: PubMed Central - HTML - PubMed

Affiliation: Novartis Pharma AG, Basel, Switzerland. didier.renard@novartis.com

ABSTRACT

Background: Indacaterol is a once-daily long-acting inhaled β2-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.

Methods: 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.

Results: 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 μg once daily, and showed that doses of 75 μg and above achieved clinically important improvements in predicted trough FEV1 response. Indacaterol 75 μg 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; ≥120 mL vs placebo), with a 90% probability that the mean improvement vs placebo exceeded the MCID. Indacaterol 150 μg 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 μg 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 μg 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.

Conclusions: Comprehensive assessment of the bronchodilatory dose response of indacaterol in COPD patients provided a robust confirmation that 75 μg is the minimum effective dose, and that 150 and 300 μg are expected to provide optimal bronchodilation, particularly in patients with severe disease.

Show MeSH
Related in: MedlinePlus