Systemic pharmacokinetics of indacaterol, an inhaled once-daily long-acting beta2-agonist, in different ethnic populations.

RATIONALE: To assess ethnic sensitivity of indacaterol systemic pharmacokinetics in Japanese vs. non-Japanese patients. METHODS: Analyses were in three parts: data from a single "all Asian" clinical study; and two on pooled data - one using a linear mixed effects (LME) model and the other a non-linear mixed effects (NLME) model. The NLME model analyzed pharmacokinetic data from nine indacaterol studies; the LME model analyzed peak (C(max)) and trough (C(min)) serum concentration using data from four of these studies. RESULTS: In the all-Asian study, indacaterol serum concentration-time pharmacokinetic profiles in Japanese patients (n = 102) were similar to those in the overall population (n = 229). In the LME model, C(max) (4,392 observations, 1,845 patients) and C(min) (4,664 observations, 1,796 patients) for Japanese patients (n = 94) were on average 25% and 18% higher, respectively, than non-Japanese patients. However, after adjusting for study differences, this apparent ethnicity effect was not significant (p = 0.25 and 0.39, respectively). In the NLME model (25,540 observations, 2,857 patients), there was no statistically significant effect of Japanese (n = 230) ethnicity on indacaterol serum pharmacokinetics. CONCLUSION: No ethnicity effect was observed on indacaterol systemic pharmacokinetic profile for Japanese patients when compared with the overall Asian patient population or with the Caucasian patient population.

Correlating changes in lung function with patient outcomes in chronic obstructive pulmonary disease: a pooled analysis.

BACKGROUND: Relationships between improvements in lung function and other clinical outcomes in chronic obstructive pulmonary disease (COPD) are not documented extensively. We examined whether changes in trough forced expiratory volume in 1 second (FEV(1)) are correlated with changes in patient-reported outcomes. METHODS: Pooled data from three indacaterol studies (n = 3313) were analysed. Means and responder rates for outcomes including change from baseline in Transition Dyspnoea Index (TDI), St. George's Respiratory Questionnaire (SGRQ) scores (at 12, 26 and 52 weeks), and COPD exacerbation frequency (rate/year) were tabulated across categories of ΔFEV(1). Also, generalised linear modelling was performed adjusting for covariates such as baseline severity and inhaled corticosteroid use. RESULTS: With increasing positive ΔFEV(1), TDI and ΔSGRQ improved at all timepoints, exacerbation rate over the study duration declined (P < 0.001). Individual-level correlations were 0.03-0.18, but cohort-level correlations were 0.79-0.95. At 26 weeks, a 100 ml increase in FEV(1) was associated with improved TDI (0.46 units), ΔSGRQ (1.3-1.9 points) and exacerbation rate (12% decrease). Overall, adjustments for baseline covariates had little impact on the relationship between ΔFEV(1) and outcomes. CONCLUSIONS: These results suggest that larger improvements in FEV(1) are likely to be associated with larger patient-reported benefits across a range of clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT00393458, NCT00463567, and NCT00624286.

Population pharmacodynamic model of the longitudinal FEV1 response to an inhaled long-acting anti-muscarinic in COPD patients.

The precise assessment of the dose-response to bronchodilators in the treatment of chronic obstructive pulmonary disease is hindered by the low signal to noise ratio of the typical clinical endpoint FEV(1). Kinetic-pharmacodynamic (K-PD) models which use time course of response over a range of doses are in principle suited for the assessment of the dose response relationship of pulmonary administered drugs. A K-PD model was successfully developed using the longitudinal FEV1 data collected in the clinical study for a novel bronchodilator X. A superposition of two cosine functions was selected to describe the circadian variability in FEV(1) at baseline. The onset (ka) and offset (kde) of drug action were described with first-order rate constants of 0.214/h and 0.141/h, respectively. Drug potency, EKD(50,) was estimated as 6.56 µg/h, and the maximum response, Emax as 0.631 L. Between-subject variability for kde, EKD(50) and Emax were 65, 84.7 or 34.4% (expressed as coefficient variation). The model-based simulation predicted that for the same total daily dose of once-daily and twice-daily regimens, the trough FEV(1) response to a twice-daily regimen was higher, and the maximum FEV(1) response to once-daily regimen was higher, while the predicted average FEV(1) response was about the same.