PMID- 21518459
OWN - NLM
STAT- MEDLINE
DCOM- 20110909
LR  - 20231105
IS  - 1465-993X (Electronic)
IS  - 1465-9921 (Linking)
VI  - 12
DP  - 2011 Apr 26
TI  - Characterization of the bronchodilatory dose response to indacaterol in patients 
      with chronic obstructive pulmonary disease using model-based approaches.
PG  - 54
LID - 10.1186/1465-9921-12-54 [doi]
AB  - BACKGROUND: 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. 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 mug once daily, and showed that 
      doses of 75 mug and above achieved clinically important improvements in predicted 
      trough FEV1 response. Indacaterol 75 mug 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 mug 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 mug 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 mug 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 mug is the 
      minimum effective dose, and that 150 and 300 mug are expected to provide optimal 
      bronchodilation, particularly in patients with severe disease.
FAU - Renard, Didier
AU  - Renard D
AD  - Novartis Pharma AG, Basel, Switzerland. didier.renard@novartis.com
FAU - Looby, Michael
AU  - Looby M
FAU - Kramer, Benjamin
AU  - Kramer B
FAU - Lawrence, David
AU  - Lawrence D
FAU - Morris, David
AU  - Morris D
FAU - Stanski, Donald R
AU  - Stanski DR
LA  - eng
PT  - Journal Article
PT  - Meta-Analysis
PT  - Research Support, Non-U.S. Gov't
DEP - 20110426
PL  - England
TA  - Respir Res
JT  - Respiratory research
JID - 101090633
RN  - 0 (Adrenergic beta-2 Receptor Agonists)
RN  - 0 (Bronchodilator Agents)
RN  - 0 (Indans)
RN  - 0 (Quinolones)
RN  - 8OR09251MQ (indacaterol)
SB  - IM
MH  - Adrenergic beta-2 Receptor Agonists/*administration & dosage
MH  - Bronchodilator Agents/*administration & dosage
MH  - Controlled Clinical Trials as Topic
MH  - Decision Support Techniques
MH  - Dose-Response Relationship, Drug
MH  - *Drug Dosage Calculations
MH  - Forced Expiratory Volume
MH  - Humans
MH  - Indans/*administration & dosage
MH  - Lung/*drug effects/physiopathology
MH  - *Nonlinear Dynamics
MH  - Pulmonary Disease, Chronic Obstructive/*drug therapy/physiopathology
MH  - Quinolones/*administration & dosage
MH  - Severity of Illness Index
MH  - Time Factors
MH  - Treatment Outcome
PMC - PMC3102616
EDAT- 2011/04/27 06:00
MHDA- 2011/09/10 06:00
CRDT- 2011/04/27 06:00
PHST- 2011/02/03 00:00 [received]
PHST- 2011/04/26 00:00 [accepted]
PHST- 2011/04/27 06:00 [entrez]
PHST- 2011/04/27 06:00 [pubmed]
PHST- 2011/09/10 06:00 [medline]
AID - 1465-9921-12-54 [pii]
AID - 10.1186/1465-9921-12-54 [doi]
PST - epublish
SO  - Respir Res. 2011 Apr 26;12:54. doi: 10.1186/1465-9921-12-54.